Benzazepine compound

ABSTRACT

Provided is a compound which is useful as an agent for treating or preventing 5-HT 2C  receptor-related diseases, particularly incontinence such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, and the like, sexual dysfunction such as erectile dysfunction syndrome and the like, obesity, and the like. The present inventors have investigated compounds having a 5-HT 2C  receptor agonist activity and have found that the benzazepine compounds of the present invention have an excellent 5-HT 2C  receptor agonist activity, thereby completing the present invention. That is, the benzazepine compounds of the present invention have a 5-HT 2C  receptor agonist activity and can be used as an agent for treating or preventing 5-HT 2C  receptor-related diseases, particularly incontinence such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, and the like, sexual dysfunction such as erectile dysfunction syndrome and the like, obesity, and the like.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.13/044,080 filed on Mar. 9, 2011, which claims the benefit of U.S.Provisional Application. No. 61/313,133 filed on Mar. 12, 2010. Thisapplication also is a continuation-in-part of U.S. application Ser. No.13/583,410 filed on Sep. 7, 2012, which is a U.S. national-stage ofInternational Application No. PCT/JP2011/055759 filed on Mar. 11, 2011,which claims the benefit of U.S. Provisional Application. No. 61/313,133filed on Mar. 12, 2010. The entire disclosures of U.S. application Ser.No. 13/044,080 and U.S. application Ser. No. 13/583,410 are incorporatedby reference herein.

TECHNICAL FIELD

The present invention relates to a benzazepine compound which is usefulas an active ingredient of a pharmaceutical composition, particularly apharmaceutical composition for treating or preventing 5-HT_(2C)receptor-related diseases, particularly incontinence such as stressurinary incontinence, urge urinary incontinence, mixed urinaryincontinence, and the like, sexual dysfunction such as erectiledysfunction syndrome and the like, obesity, and the like.

BACKGROUND ART

A serotonin 2C (5-HT_(2C)) receptor is one of the receptors forserotonin, a transmitter related to various physiological functions inthe biological body. Its expression has been recognized mainly in thecentral nervous system (brain/spinal cord).

An anorectic action is known as a physiological function of the central5-HT_(2C) receptor, and the lowering action of various 5-HT_(2C)receptor agonists on food intake has been reported in rats (Non-PatentDocuments 1 and 2). Further, it has been confirmed that an anti-obesityaction in humans is exhibited due to the anorectic action of the5-HT_(2C) receptor agonist (Non-Patent Document 3).

The central 5-HT_(2C) receptor is involved in the control of peripheralnerve functions and it has been reported that the rat penile erection isinduced by a 5-HT_(2C) receptor agonist (Non-Patent Document 4) and thatthe time taken from insertion to ejaculation in the experiment formating behavior of monkeys is prolonged (Non-Patent Document 5).Moreover, it has been reported that a 5-HT_(2C) receptor agonistincreases the urethral resistance when the abdominal pressure isincreased in rats (Non-Patent Document 6). In addition, it has beenreported that in disease models with neuropathic/inflammatory pain inrats, efficacy is exhibited by intraspinal administration of a 5-HT_(2C)receptor agonist (Non-Patent Documents 7 and 8). Various clinicalapplications are considered for 5-HT_(2C) receptor agonists,particularly as anti-obesity drugs, drugs for treating male erectiledysfunction, drugs for treating premature ejaculation, drugs fortreating stress urinary incontinence, drugs for treatingneuropathic/inflammatory pain, or the like.

As the 5-HT_(2C) receptor agonist, a benzazepine derivative has beenreported, and as a tricyclic benzazepine derivative, for example,Compound A (Patent Document 1) and Compound B (Patent Document 2) areknown.

As other 5-HT_(2C) receptor agonists, bicyclic benzazepine derivativeshave been reported (Patent Document 3, Patent Document 4, and PatentDocument 5).

As a 2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline derivative ora 3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine derivative,which is a tricyclic benzazepine derivative, a compound of the formula(AA) is known to be a Dopamine D3 modulator and be useful for centraldrug abuse and drug dependence (Patent Document 6).

In addition, in this document, the following compounds are disclosed asa synthetic intermediate for the formula (AA).

Furthermore, there is a report on the structure-activity relationship ofa specific compound of the formula (AA) (Non-Patent Document 9), and inthis report, it is described that the following compound was used in thepreparation of the compound of the formula (AA).

Moreover, there is a report on a 5-HT₆ receptor antagonist (Non-PatentDocument 10), and it is disclosed that for the compound below, potencyon the 5-HT₆ receptor is lost by changing a ring condensed withbenzazepine from a 5-membered ring to a 6-membered ring.

However, in the documents which disclose such tricyclic benzazepinederivatives, there is no disclosure on the 5-HT_(2C) receptor agonistactivity of the 2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinolinederivative or the3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine derivative.

PRIOR ART DOCUMENT Patent Document

-   [Patent Document 1] WO 2002/074746-   [Patent Document 2] WO 2003/086306-   [Patent Document 3] WO 2005/042490-   [Patent Document 4] WO 2005/042491-   [Patent Document 5] WO 2005/003096-   [Patent Document 6] WO 2005/118549

Non-Patent Document

-   [Non-Patent Document 1] Obesity, 2008, vol. 17, pp. 494-503-   [Non-Patent Document 2] Progress in Neuro-Psychopharmacology and    Biological Psychiatry, 2002, vol. 26, pp. 441-449-   [Non-Patent Document 3] Journal of Pharmacology and Experimental    Therapeutics, 2008, vol. 325, pp. 577-587-   [Non-Patent Document 4] European Journal of Pharmacology, 2004, vol.    483, pp. 37-43-   [Non-Patent Document 5] Psychopharmacology, 1993, vol. 111, pp.    47-54-   [Non-Patent Document 6] American Journal of Physiology: Renal    Physiology, 2009, vol. 297, pp. 1024-1031-   [Non-Patent Document 7] Pain, 2004, vol. 108, pp. 163-169-   [Non-Patent Document 8] Anesthesia and Analgesia, 2003, vol. 96, pp.    1072-1078-   [Non-Patent Document 9] Bioorganic & Medicinal Chemistry Letters,    2008, vol. 18, pp. 901-907-   [Non-Patent Document 10] Bioorganic & Medicinal Chemistry Letters,    2008, vol. 18, pp. 5698-5700

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

A benzazepine compound which is useful as an active ingredient for apharmaceutical composition, particularly a pharmaceutical compositionfor treating or preventing 5-HT_(2C) receptor-related diseases,particularly incontinence such as stress urinary incontinence, urgeurinary incontinence, mixed urinary incontinence, and the like, sexualdysfunction such as erectile dysfunction syndrome and the like, obesity,and the like is provided.

Means for Solving the Problem

The present inventors have extensively studied compounds having a5-HT_(2C) receptor agonist activity, and as a result, they have foundthat the benzazepine compound of the present invention has a 5-HT_(2C)receptor agonist activity, thereby completing the present invention.

That is, the present invention relates to a pharmaceutical compositionincluding the compound of the formula (I) or a salt thereof and apharmaceutically acceptable excipient.

(wherein

R^(1a) and R^(1b) are the same or different and each represents or C₁₋₆alkyl, or are combined to form oxo,

R^(2a) and R^(2b) are the same or different and each represents —H orC₁₋₆ alkyl which may be substituted with —O—C₁₋₆ alkyl,

R³ represents —H, C₁₋₆ alkyl which may be substituted, C₃₋₈ cycloalkyl,aryl which may be substituted, —SO₂—C₁₋₆ alkyl, or a hetero ring whichmay be substituted,

R⁴ represents —H, halogen, cyano, C₁₋₆ alkyl which may be substituted,C₂₋₆ alkenyl, aryl which may be substituted, C₃₋₈ cycloalkyl which maybe substituted, an aromatic hetero ring, or an oxygen-containing heteroring,

R⁵ represents —H, halogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl, or anaromatic hetero ring,

R⁶ and R⁷ are the same or different and each represents —H or C₁₋₆alkyl,

X represents —C(R^(A))(R^(B))— or —O—, and

R^(A) and R^(B) are the same or different and each represents —H or C₁₋₆alkyl.)

Furthermore, the present invention relates to a compound of the formula(II) or a salt thereof.

(wherein

R^(11a) and R^(11b) are the same or different and each represents —H orC₁₋₆ alkyl, or are combined to form oxo,

R^(21a) and R^(21b) are the same or different and each represents —H orC₁₋₆ alkyl which may be substituted with —O—C₁₋₆ alkyl,

R³¹ represents —H, C₁₋₆ alkyl which may be substituted, C₃₋₈ cycloalkyl,aryl which may be substituted, —SO₂—C₁₋₆ alkyl, or a hetero ring whichmay be substituted,

R⁴¹ represents —H, halogen, cyano, C₁₋₆ alkyl which may be substituted,C₂₋₆ alkenyl, aryl which may be substituted, C₃₋₈ cycloalkyl which maybe substituted, an aromatic hetero ring, or an oxygen-containing heteroring,

R⁵¹ represents —H, halogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, aryl, or anaromatic hetero ring,

R⁶¹ and R⁷¹ are the same or different and each represents —H or C₁₋₆alkyl,

X¹ represents —C(R^(A1))(R^(B1))— or —O—, and

R^(A1) and R^(B1) are the same or different and each represents —H orC₁₋₆ alkyl, provided that

(i) in the case where R^(11a), R^(11b), R^(21a), R^(21b), R⁴¹, R⁵¹, R⁶¹,and R⁷¹ are respectively —H and X¹ is —O—, R³¹ is a group other than —H,—CO-methyl, or —SO₂-methyl, and

(ii) in the case where R^(11a) and R^(11b) are combined to form oxo,R^(21a), R^(21b), R⁴¹, R⁵¹, R⁶¹, and R⁷¹ are respectively —H, and X¹ is—O—, R³¹ is a group other than —H or methyl.)

Furthermore, in the case where the symbols in any of the formulas in thepresent specification are also used in other formulas, the same symbolsdenote the same meanings, unless specifically described otherwise.

Furthermore, the present invention relates to a pharmaceuticalcomposition for preventing or treating 5-HT_(2C) receptor-relateddiseases, including the compound of the formula (I) or a salt thereof,or the compound of the formula (II) or a salt thereof. In thisconnection, the pharmaceutical composition includes an agent forpreventing or treating 5-HT_(2C) receptor-related diseases, includingthe compound of the formula (I) or a salt thereof, or the compound ofthe formula (II) or a salt thereof.

Moreover, the present invention relates to use of the compound of theformula (I) or a salt thereof, or the compound of the formula (II) or asalt thereof for preparation of a pharmaceutical composition forpreventing or treating 5-HT_(2C) receptor-related diseases; the compoundof the formula (I) or a salt thereof, or the compound of the formula(II) or a salt thereof for prevention or treatment of 5-HT_(2C)receptor-related diseases; and a method for preventing or treating5-HT_(2C) receptor-related diseases, including administering to asubject an effective amount of the compound of the formula (I) or a saltthereof, or the compound of the formula (II) or a salt thereof. Inaddition, the “subject” is human or other animals in need of theprevention or treatment, and in a certain embodiment, human in need ofthe prevention or treatment.

In addition, the compound of the formula (II) or a salt thereof isincluded in the compound of the formula (I) or a salt thereof.Accordingly, in the present specification, the explanation of thecompound of the formula (I) includes that of the compound of the formula(II).

Effects of the Invention

The compound of the formula (I) or a salt thereof, or the compound ofthe formula (II) or a salt thereof has a 5-HT_(2C) receptor agonistactivity and can be used as an agent for preventing or treating5-HT_(2C) receptor-related diseases.

Here, examples of the 5-HT_(2C) receptor-related diseases includeincontinence such as stress urinary incontinence, urge urinaryincontinence, mixed urinary incontinence, and the like, sexualdysfunction such as erectile dysfunction syndrome and the like, obesity,and the like.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the present specification, the “alkyl” includes straight alkyl andbranched alkyl. Accordingly, the “C₁₋₆ alkyl” is a straight or branchedalkyl having 1 to 6 carbon atoms, and specific examples thereof includemethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, andthe like, in another embodiment, methyl, ethyl, propyl, isopropyl, in afurther embodiment, methyl, ethyl, in a still further embodiment,methyl, and in a still further embodiment, ethyl.

The “alkylene” is a divalent group formed by the removal of any onehydrogen atom of the “alkyl” above. Accordingly, the “C₁₋₆ alkylene” isstraight or branched alkylene having 1 to 6 carbon atoms, and specificexamples thereof include methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, methylmethylene,dimethylmethylene, ethylmethylene, methylethylene, dimethylethylene,ethylethylene, and the like, in another embodiment, methylene, ethylene,and in a further embodiment methylene.

The “aryl” is a monocyclic to tricyclic aromatic hydrocarbon ring grouphaving 6 to 14 carbon atoms. Specific examples thereof include phenyland naphthyl, in another embodiment, phenyl, and in a furtherembodiment, naphthyl.

The “cycloalkyl” is a saturated hydrocarbon ring group, the cycloalkylmay have a bridge and may be condensed with a benzene ring, and a partof the bonds may be unsaturated. Accordingly, specific examples of the“C₃₋₈ cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclooctadienyl,norbornyl, bicyclo[2.2.2]octyl, indanyl, indenyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and the like.

The “hetero ring” is a monovalent group of a 3- to 15-membered, inanother embodiment, a 5- to 10-membered, monocyclic to tricyclicheterocyclic group containing 1 to 4 hetero atoms selected from oxygen,sulfur, and nitrogen, and includes a saturated ring, an aromatic ring,and a partially hydrogenated ring group thereof. The ring atom, sulfuror nitrogen, may be oxidized to form an oxide or a dioxide. Specificexamples thereof include monocyclic aromatic hetero rings such aspyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, andthe like, bicyclic aromatic hetero rings such as indolyl, isoindolyl,benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl,benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolyl,isoquinolyl, quinoxalinyl, quinazolinyl, phthalazinyl,benzothiadiazolyl, and the like, tricyclic aromatic hetero rings such ascarbazolyl, dibenzo[b,d]furanyl, dibenzo[b,d]thienyl, and the like,monocyclic non-aromatic hetero rings such as azetidinyl, pyrrolidinyl,piperidyl, piperazinyl, azepanyl, diazepanyl, morpholinyl,thiomorpholinyl, tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, dioxolanyl, dioxanyl, tetrahydrothiopyranyl, and thelike, bicyclic non-aromatic hetero rings such as indolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzimidazolyl,tetrahydrobenzimidazolyl, tetrahydroquinoxalinyl, dihydroquinoxalinyl,dihydrobenzoxazolyl, dihydrobenzoxazinyl, dihydrobenzofuryl, chromanyl,chromenyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like,bridged hetero rings such as quinuclidinyl and the like, in anotherembodiment, a 5- to 10-membered monocyclic to bicyclic hetero ring, in afurther embodiment, a 5- to 6-membered monocyclic hetero ring, and in astill further embodiment, a 5- to 6-membered mono cyclic aromatic heteroring.

The “aromatic hetero ring” is a 5- to 10-membered monocyclic to bicyclicaromatic hetero ring among the “hetero rings” above, and specificexamples thereof include pyrrolyl, furyl, thienyl, pyrazolyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl,benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl,phthalazinyl, and the like, and in another embodiment, furyl, thienyl,pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, and pyrazyl.

The “cyclic amino” is a 5- to 7-membered non-aromatic hetero ring havinga binding position at a nitrogen atom among the “hetero rings” above,and specific examples thereof include pyrrolidinyl, piperidyl,piperazinyl, azepanyl, diazepanyl, morpholinyl, and thiomorpholinyl.

The “oxygen-containing hetero ring” is a monovalent group of anon-aromatic 5- to 6-membered ring which may be condensed with a benzenering having one or two oxygen atoms as ring-constituting atoms. Specificexamples thereof include tetrahydropyranyl, tetrahydropyranyl,dioxolanyl, dioxanyl, dihydrobenzofuranyl, dihydrochromenyl,benzodioxolyl, benzodioxinyl, dihydrodioxinyl, dihydrobenzodioxinyl,dihydropyranyl, dioxinyl, chromenyl, and benzodioxinyl.

The “halogen” means —F, —Cl, —Br, or —I, and in another embodiment, —F,—Cl, or —Br.

The “halogeno-C₁₋₆ alkyl” is C₁₋₆ alkyl substituted with one or morehalogen atoms, and specific examples thereof include fluoromethyl,difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl,chloroethyl, bromoethyl, fluoropropyl, dichloropropyl,fluorochloropropyl, and the like, and in another embodiment,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoro ethyl, andfluoropropyl.

In the present specification, the expression “which may be substituted”means unsubstituted or substituted with 1 to 5 substituents. Further, ifit has a plurality of substituents, the substituents may be the same asor different from each other.

Specific examples of the substituent for the “C₁₋₆ alkyl which may besubstituted”, “C₁₋₆ alkylene which may be substituted”,“(C₃₋₈)cycloalkyl which may be substituted”, “aryl which may besubstituted”, or “hetero ring which may be substituted” of R³ and R⁴include amino, nitro, cyano, halogen, C₁₋₆ alkyl, halogeno-C₁₋₆ alkyl,—OH, —C₁₋₆ alkylene-OH, —O—C₁₋₆ alkyl, —C₁₋₆ alkylene-O—C₁₋₆ alkyl,—C₁₋₆ alkylene-cycloalkyl, —C₁₋₆ alkylene-aryl, —C₁₋₆ alkylene-heteroring, —CO—C₁₋₆ alkyl, —CO—C₁₋₆ alkylene-O—C₁₋₆ alkyl, —CO-cycloalkyl,—CO-aryl, —CO—NR⁸R⁹, —CO—O—C₁₋₆ alkyl, —CO—O—C₁₋₆ alkylene-aryl,—SO₂—C₁₋₆ alkyl, aryl, a hetero ring, and the like.

Here, R⁸ and R⁹ are the same or different and each represents —H or C₁₋₆alkyl.

In another embodiment, examples of the substituent for “C₁₋₆ alkyl whichmay be substituted” in R³ include:

(1) halogen,

(2) oxo, —OH, and —O—R^(Z),

(3) —O-(phenyl which may be substituted with one or more groups selectedfrom the group consisting of R^(Z), —O—R^(Z), halogen, and cyano),

(4) —O-aromatic hetero ring,

(5) amino which may be substituted with one or two R^(Z),

(6) phenyl which may be substituted with one or more groups selectedfrom the group consisting of R^(Z), —O—R^(Z), halogen, and cyano,

(7) C₃₋₄ cycloalkyl which may be substituted with R^(Z),

(8) an oxygen-containing hetero ring which may be substituted withhalogen,

(9) a cyclic amino which may be substituted with R^(Z), and

(10) an aromatic hetero ring,

in which the C₁₋₆ alkyl may be substituted with one or moresubstituents.

Furthermore, R^(Z) herein represents C₁₋₆ alkyl which may be substitutedwith one or more groups selected from the group consisting of halogen,—O—C₁₋₆ alkyl, C₃₋₄ cycloalkyl, and phenyl (in which the phenyl may besubstituted with one or more groups selected from the group consistingof halogen and —O—C₁₋₆ alkyl).

In another embodiment, examples of the substituent for the “aryl whichmay be substituted” in R³ include halogen, and the aryl may besubstituted with one or more substituents.

In a further embodiment, examples of the substituent for the “C₁₋₆ alkylwhich may be substituted” in R⁴ include halogen and aryl, and the C₁₋₆alkyl may be substituted with one or more substituents.

In a still further embodiment, examples of the substituent of the “arylwhich may be substituted” in R⁴ include halogen, C₁₋₆ alkyl, and —O—C₁₋₆alkyl, and the aryl may be substituted with one or more substituents.

Some embodiments of the compound of the formula (I) or a salt thereofare presented below.

(1) The compound or a salt thereof, wherein R^(1a) and R^(1b) are thesame or different and each represents —H or methyl. In anotherembodiment, the compound or a salt thereof, wherein R^(1a) and R^(1b)are respectively —H. In a further embodiment, the compound or a saltthereof, wherein R^(1a) is —H and R^(1b) is methyl. In a still furtherembodiment, the compound or a salt thereof, wherein R^(1a) and R^(1b)are combined to form oxo.

(2) The compound or a salt thereof, wherein R^(2a) is —H and R^(2b) is—H or C₁₋₆ alkyl. In another embodiment, the compound or a salt thereof,wherein R^(2a) is —H and R^(2b) is —H or methyl. In a furtherembodiment, the compound or a salt thereof, wherein R^(2a) and R^(2b)are respectively —H.

(3) The compound or a salt thereof, wherein R³ is C₁₋₆ alkyl which maybe substituted with one or more groups selected from the groupconsisting of (a) to (e) below:

(a) halogen, (b) —O—C₁₋₆ alkyl, (c) phenoxy which may be substitutedwith one or more groups selected from the group consisting of halogenand cyano, (d) an oxygen-containing hetero ring, and (e) phenyl whichmay be substituted with one or more groups selected from the groupconsisting of C₁₋₆ alkyl which may be substituted with —O—C₁₋₅ alkyl,halogen, and —O—C₁₋₆ alkyl.

In another embodiment, the compound or a salt thereof, wherein R³ isC₁₋₆ alkyl which may be substituted with one or more groups selectedfrom the group consisting of (f) to (j) below:

(f) fluoro, (g) methoxy, ethoxy, (h) phenoxy which may be substitutedwith one or more groups selected from the group consisting of fluoro andcyano, (i) tetrahydrofuranyl, tetrahydropyranyl, ordihydrobenzodioxinyl, and (j) phenyl which may be substituted with oneor more groups selected from the group consisting of fluoro, chloro,methyl, and methoxymethyl.

In another embodiment, the compound or a salt thereof, wherein R³ isisobutyl. In another embodiment, the compound or a salt thereof, whereinR³ is ethyl or propyl, which respectively is substituted with one ormore groups selected from the group consisting of fluoro, methoxy, andethoxy. In a further embodiment, the compound or a salt thereof, whereinR³ is ethyl substituted with phenoxy which may be substituted with oneor more groups selected from the group consisting of fluoro and cyano.In a still further embodiment, the compound or a salt thereof, whereinR³ is methyl substituted with a group selected from the group consistingof tetrahydrofuranyl, tetrahydropyranyl and dihydrobenzodioxinyl. In astill further embodiment, the compound or a salt thereof, wherein R³ ismethyl substituted with phenyl which may be substituted with one or moregroups selected from the group consisting of fluoro, chloro, methyl, andmethoxymethyl.

(4) The compound or a salt thereof, wherein R⁴ is —H, halogen, or C₃₋₈cycloalkyl. In another embodiment, the compound or a salt thereof,wherein R⁴ is —H, bromo, or cyclopropyl. In a further embodiment, thecompound or a salt thereof, wherein R⁴ is —H. In a further embodiment,the compound or a salt thereof, wherein R⁴ is bromo. In a still furtherembodiment, the compound or a salt thereof, wherein R⁴ is cyclopropyl.

(5) The compound or a salt thereof, wherein R⁵ is —H or C₁₋₆ alkyl. Inanother embodiment, the compound or a salt thereof, wherein R⁵ is —H ormethyl. In a further embodiment, the compound or a salt thereof, whereinR⁵ is —H.

(6) The compound or a salt thereof, wherein R⁶ and R⁷ are the same ordifferent and each represents —H or methyl. In another embodiment, thecompound or a salt thereof, wherein R⁶ is methyl and R⁷ is —H. In afurther embodiment, the compound or a salt thereof, wherein R⁶ is —H andR⁷ is methyl. In a still further embodiment, the compound or a saltthereof, wherein R⁶ and R⁷ are respectively —H.

(7) The compound or a salt thereof, wherein X is —C₂— or —O—. In anotherembodiment, the compound or a salt thereof, wherein X is —CH₂—. In afurther embodiment, the compound or a salt thereof, wherein X is —O—.

(8) The compound or a salt thereof, which is a combination of two ormore of (1) to (7) as described above.

The compound or a salt thereof as described above in (8), which is acombination of two or more of (1) to (7) as described above, is includedin the present invention, and the following embodiments including thespecific examples thereof can be exemplified as below.

(9) The compound or a salt thereof, wherein R³ is —H, C₁₋₆ alkyl whichmay be substituted, C₃₋₈ cycloalkyl, aryl which may be substituted,—SO₂—C₁₋₆ alkyl, or an oxygen-containing hetero ring, and R⁴ is —H,halogen, cyano, C₁₋₆ alkyl which may be substituted, C₂₋₆ alkenyl, arylwhich may be substituted, C₃₋₄ cycloalkyl, an aromatic hetero ring, oran oxygen-containing hetero ring.

(10) The compound or a salt thereof as described in (9), wherein R³ is agroup other than —H, methyl, —CO-methyl, or —SO₂— methyl.

(11) The compound or a salt thereof as described in (10), wherein R^(1a)is —H or methyl, and R^(1b), R^(2a), R^(2b), R⁵, R⁶, and R⁷ arerespectively —H.

(12) The compound or a salt thereof as described in (11), wherein R⁴ is—H, halogen, or C₃₋₄ cycloalkyl.

(13) The compound or a salt thereof as described in (12), wherein R⁴ iscyclopropyl.

(14) The compound or a salt thereof as described in (13), wherein R³ isC₁₋₆ alkyl which may be substituted with one or more groups selectedfrom the group consisting of (a) halogen, (b) —O—C₁₋₆ alkyl, (c) phenoxywhich may be substituted with one or more groups selected from the groupconsisting of halogen and cyano, (d) an oxygen-containing hetero ring,and (e) phenyl which may be substituted with one or more groups selectedfrom the group consisting of C₁₋₆ alkyl which may be substituted with—O—C₁₋₆ alkyl, halogen, and —O—C₁₋₆ alkyl.

(15) The compound or a salt thereof as described in any one of (1) to(14), wherein

X is —CH₂— or —O—. In another embodiment, the compound or a salt thereofas described in any one of (1) to (14), wherein X is —O—. In a stillfurther embodiment, the compound or a salt thereof as described in anyone of (1) to (14), wherein X is —CH₂—.

Examples of the specific compounds included in the compound of theformula (I) or a salt thereof include:

-   11-cyclopropyl-1-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline,-   4-(3-methoxypropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2-ethoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(3-methoxypropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(3-fluoropropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   1-isobutyl-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline,-   5-bromo-4-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-[(2R)-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2-fluorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-[(2S)-3-fluoro-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   4-(3-chlorobenzyl)-5-cyclopropyl-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(tetrahydro-2H-pyran-3-ylmethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2-phenoxyethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2-methylbenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(3-methylbenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2,5-difluorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-[3-(methoxymethyl)benzyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   4-(5-chloro-2-fluorobenzyl)-5-cyclopropyl-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   (3S)-5-cyclopropyl-4-(2-methoxyethyl)-3-methyl-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   4-[2-(5-cyclopropyl-2,3,7,8,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepin-4(6H)-yl)ethoxy]-3,5-difluorobenzonitrile,-   5-cyclopropyl-4-(3-methoxybenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,-   5-cyclopropyl-4-(3,5-difluorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,    and-   5-cyclopropyl-4-[(2R)-2-ethoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,    and salts thereof.

The compound of the formula (I) may exist in the form of tautomers orgeometrical isomers depending on the kind of substituents. In thepresent specification, the compound of the formula (I) shall bedescribed in only one form of isomer, yet the present invention includesother isomer, such as an isolated forms of the isomers, or a mixturethereof.

In addition, the compound of the formula (I) may have asymmetric carbonatoms or axial asymmetry in some cases, and correspondingly, it mayexist in the form of optical isomers. The present invention includesboth an isolated form of the optical isomers of the compound of theformula (I) or a mixture thereof.

Moreover, the present invention also includes a pharmaceuticallyacceptable prodrug of the compound of the formula (I). Thepharmaceutically acceptable prodrug is a compound having a group thatcan be converted into an amino group, a hydroxyl group, a carboxylgroup, or the like through solvolysis or under physiological conditions.Examples of the group forming the prodrug include the groups describedin Prog. Med., 5, 2157-2161 (1985) and Pharmaceutical Research andDevelopment, Drug Design, Hirokawa Publishing Company (1990), vol. 7,163-198.

Moreover, the salt of the compound of the formula (I) is apharmaceutically acceptable salt of the compound of the formula (I) andmay form an acid addition salt or a salt with a base depending on thekind of substituents. Specific examples thereof include acid additionsalts with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, and with organic acids such as formic acid, acetic acid, propionicacid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleicacid, lactic acid, malic acid, mandelic acid, tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, andsalts with inorganic bases such as sodium, potassium, magnesium,calcium, aluminum, and the like or organic bases such as methylamine,ethylamine, ethanolamine, lysine, ornithine, and the like, salts withvarious amino acids or amino acid derivatives such as acetylleucine andthe like, ammonium salts, etc.

In addition, the present invention also includes various hydrates orsolvates, and polymorphic crystal substances of the compound of theformula (I) and a salt thereof. In addition, the present invention alsoincludes compounds labeled with various radioactive or non-radioactiveisotopes.

(Preparation Methods)

The compound of the formula (I) and a salt thereof can be prepared usingthe characteristics based on the basic structure or the type ofsubstituents thereof and by applying various known synthesis methods.During the preparation, replacing the relevant functional group with asuitable protective group (a group that can be easily converted into thefunctional group) at the stage from starting material to an intermediatemay be effective depending on the type of the functional group inproduction technology in some cases. The protective group for such afunctional group may include, for example, the protective groupsdescribed in “Greene's Protective Groups in Organic Synthesis (4^(th)Ed., 2006)” written by P. G. M. Wuts and T. W. Greene, and one of thesemay be selected and used as necessary depending on the reactionconditions. In this kind of method, a desired compound can be obtainedby introducing the protective group, by carrying out the reaction and byeliminating the protective group as necessary.

In addition, the prodrug of the compound of the formula (I) can beproduced by introducing a specific group or by carrying out the reactionusing the obtained compound of the formula (I) at the stage from astarting material to an intermediate, just as in the case of theabove-mentioned protective group. The reaction can be carried out usingmethods known to those skilled in the art, such as ordinaryesterification, amidation, dehydration, and the like.

Hereinbelow, the representative preparation methods for the compound ofthe formula (I) will be described. Each of the production processes mayalso be carried out with reference to the References appended in thepresent description. Further, the preparation methods of the presentinvention are not limited to the examples as shown below.

The compound of the formula (I) can be obtained by removing P which is aprotective group for an amino group. The protective group for P may beany protective group for an amino group which is usually used by aperson skilled in the art, and carbonyl such as trifluoroacetyl and thelike; oxycarbonyl such as t-butoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, and the like; or sulfonyl such as methanesulfonyl,p-toluenesulfonyl, trifluoromethanesulfonyl, p-nitrophenylsulfonyl,2,4-dinitrophenylsulfonyl, and the like is suitably used.

For the deprotection in the present step, the conditions fordeprotection usually used by a person skilled in the art can beemployed. For example, preparation can be performed by acid treatment,hydrolysis, hydrogenolysis, or the like. For acid treatment, forexample, trifluoroacetic acid, hydrochloric acid, sulfuric acid, or thelike can be used. In the case of alkali hydrolysis, inorganic bases (forexample NaOH, KOH, NaHCO₃, Cs₂CO₃, and the like) can be used. In thecase of acid hydrolysis, hydrochloric acid and the like can be used. Forany reaction temperature, the reaction can be performed under thecondition from under ice-cooling to under refluxing and under thecondition which does not allow the substrate to be decomposed. As thesolvent, dioxane, tetrahydrofuran, dichloromethane, chloroform, ethylacetate, alcohols (MeOH, EtOH, and the like), N,N-dimethylformamide(DMF), dimethylsulfoxide (DMSO), water, or a mixed solvent thereof, andthe like may be used, but are not limited thereto. In the case ofhydrogenolysis, the reaction can usually be performed under a hydrogenatmosphere in the presence of a palladium catalyst. Usually, thereaction can be performed under the condition of from room temperatureto under refluxing and under the condition which does not allow thesubstrate to be decomposed. As the solvent, DMF or alcohols (MeOH, EtOH,and the like) may be used, but are not limited thereto. Further, theconditions for the de-carboxamide reaction, the de-carbamate reaction,the de-sulfonamide reaction described in “Greene's Protective Groups inOrganic Synthesis (4^(th) Ed., 2006)” above can be employed.

Various substituents defined as the groups in the compound of theformula (I), R^(1a), R^(1b), R^(2a), R^(2b), R³, R⁴, R⁵, R⁶, and R⁷ canbe easily converted to other functional groups by using the compound ofthe formula (I) as a starting material or using the syntheticintermediate of the compound of the formula (I) as a starting materialby means of the reaction described in Examples as described later, thereaction apparent to a person skilled in the art, or modified methodsthereof. For example, the step that can be usually employed by a personskilled in the art, such as O-alkylation, N-alkylation, reduction,hydrolysis, amidation, and the like can be arbitrarily combined andperformed.

(Preparation of Starting Compound)

The starting compound in the preparation method above can be preparedby, for example, the following method, the method described inPreparation Examples as described later, known methods, or modifiedmethods thereof.

(Starting Material Synthesis 1)

A compound represented by the general formula (1) which is a startingmaterial for synthesizing a compound of the general formula (2) iscommercially available or prepared by a means known to a person skilledin the art. Then, the compound of the general formula (2) can beprepared by nitrating the compound of the general formula (1). Forexample, a number of known nitration reactions can be used, examples ofwhich include a method using nitric acid, fumed nitric acid, potassiumnitrate, or the like in an acid solvent, a method using nitroniumtetrafluoroborate, and the like. Then, the compound of the generalformula (3) can be prepared by reducing a nitro group of the compound ofthe general formula (2) to an amino group. For example, a number ofknown reduction methods can be used, examples of which include a methodusing metal hydrides such as lithium aluminum hydride and the like, amethod using reduced iron or the like, and the like. Further, catalytichydrogenation using noble metal catalysts such as Raney nickel,palladium, ruthenium, rhodium, platinum, and the like can also be used.

(Starting Material Synthesis 2)

(wherein R^(Xa) is C₁₋₆ alkyl).

A compound of the general formula (4) can be prepared by halogenatingthe compound of the general formula (3). For example, a number of knownhalogenation reactions can be used, examples of which include a methodusing N-bromosuccinimide or N-chlorosuccinimide, and the like. Then, thecompound of the general formula (5) can be prepared from the compound ofthe general formula (4) by a coupling reaction using a transition metalcatalyst. Examples of the coupling reaction include a Heck reaction. Thereaction conditions for the Heck reaction vary depending on the startingmaterials, solvents, and transition metal catalysts used, and techniquesknown to a person skilled in the art can be used. Examples of thepreferred solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane orDMF, and the like, but are not limited thereto. The transition metalcatalyst is preferably a palladium complex, and more preferably knownpalladium complexes such as palladium(II) acetate,dichlorobis(triphenylphosphine)palladium(II),tetrakis(triphenylphosphine)palladium(0), and the like. Further, for thepresent reaction, a phosphorous ligand (preferably, triphenylphosphine,tri-o-tolylphosphine, tri-tert-butylphosphine,2-(di-tert-butylphosphino)biphenyl, or the like) may be added in orderto obtain excellent results. Also, the present reaction can yieldpreferable results in the presence of a base, and the base used hereinis not particularly limited as long as it is used for the couplingreaction of the present reaction, but it is preferably triethylamine,N,N-diisopropylethylamine, or the like.

(Starting Material Synthesis 3)

The compound of the general formula (IIIa) can be obtained by allowingan intramolecular amide condensation cyclization reaction to proceed bycarrying out a hydrogenation reaction of the double bond of theα,β-unsaturated esters of the compound of the general formula (5). Inthis reaction, the compound of the general formula (5) is stirred in thepresence of a metal catalyst, usually for 1 hour to 5 days, in a solventinert to the reaction, under a hydrogen atmosphere. This reaction isusually carried out in the range from cooling to heating, preferably atroom temperature. Examples of the solvent used herein are notparticularly limited, but include alcohols such as methanol, ethanol,2-propanol, and the like, ethers such as diethylether, tetrahydrofuran,dioxane, dimethoxyethane, and the like, water, ethyl acetate, DMF, DMSOand a mixture thereof. As the metal catalyst, palladium catalysts suchas palladium on carbon, palladium black, palladium hydroxide, and thelike, platinum catalysts such as a platinum plate, platinum oxide, andthe like, nickel catalysts such as reduced nickel, Raney nickel, and thelike, rhodium catalysts such as tetrakistriphenylphosphinechlororhodium, and the like, iron catalysts such as reduced iron and thelike, etc. are preferably used. Instead of hydrogen gas, formic acid orammonium formate in an equivalent amount or in an excess amount to thecompound of the general formula (5) can be used as a hydrogen source.

Furthermore, for the compound in which R^(2b) is other than —H, anR^(2b) group other than —H can be introduced to a desired position byusing an electrophilic substitution reaction to the α-position ofcarbonyl by the use of a base or by a method which can be usuallyemployed by a person skilled in the art for the compound (Ma).

REFERENCES

-   “Reductions in Organic Chemistry, 2^(nd) Ed. (ACS Monograph: 188)”    written by M. Hudlicky, ACS, 1996

(Starting Material Synthesis 4)

A compound of the general formula (IIIb) can be obtained by carrying outreduction of a carbonyl group of the compound of the general formula(IIIa). This reaction is usually carried out in the presence of areducing agent in a solvent. Examples of the solvent used herein are notparticularly limited, but include ethers such as diethylether,tetrahydrofuran, dioxane, dimethoxyethane, and the like, and aromatichydrocarbons such as benzene, toluene, xylene, and the like. Examples ofthe reducing agent include aluminum hydride compounds such as lithiumaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and thelike, and borohydride compounds such as sodium borohydride, diborane, aborane-tetrahydrofuran complex, and the like.

(Starting Material Synthesis 5)

(wherein R^(4a) represents C₁₋₆ alkyl, halogeno-C₁₋₆ alkyl, cycloalkylwhich may be substituted, or aryl which may be substituted, and Halrepresents halogen).

A compound of the general formula (IIId) can be obtained by a couplingreaction of a compound of the general formula (IIIc). For example, theSuzuki coupling described in the following references, the Heck reactiondescribed for the Starting Material Synthesis 2 above, or the like canbe employed.

REFERENCES

-   Chemical Reviews, vol. 95, No. 7, p. 2457 (1995), Journal of    American Chemical Society, vol. 127, p. 4685 (2005), Synlett, No.    13, p. 2327 (2004), Tetrahedron letters, No. 41, p. 4363 (2000), or    Tetrahedron letters, No. 43, p. 2695 (2002)

The compound of the general formula (IIId) can also be obtained by themethod described in Examples as described later.

(Starting Material Synthesis 6)

(wherein R^(3a) represents a group other than —H among the groupsdefined as R³).

A compound of the general formula (IIIe) can be obtained by alkylation,acylation, or the like of the compound of the general formula (IIIb).For the specific reaction conditions, the conditions described in thefollowing references can be employed.

REFERENCES

-   “Organic Functional Group Preparations” written by S. R. Sandler    and W. Karo, 2^(nd) Ed., vol. 1, Academic Press Inc., 1991-   “Courses in Experimental Chemistry (5^(th) Ed.)”, edited by The    Chemical Society of Japan, vol. 14 (2005) (Maruzen)

The compound of the general formula (IIIe) can also be obtained by themethod described in the Examples as described later and the methoddescribed for the Starting Material Synthesis 4 above.

(Starting Material Synthesis 7)

A compound of the general formula (8) can be obtained by the reaction ofa compound of the general formula (6) with a compound of the generalformula (7). In this regard, examples of the leaving group of L¹ includehalogen, methanesulfonyloxy, p-toluenesulfonyloxy groups, and the like.

In this reaction, the compound of the general formula (6) and thecompound of the general formula (7) are used in equivalent amounts, orwith either one of them in an excess amount, and a mixture thereof isstirred under a temperature condition from cooling to heating andrefluxing, preferably at 0° C. to 80° C., usually for 0.1 hours to 5days, in a solvent inert to the reaction in the presence of a base.Examples of the solvent used herein are not particularly limited, butinclude aromatic hydrocarbons such as benzene, toluene, xylene, and thelike, ethers such as diethylether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane, chloroform, and the like, DMF,DMSO, ethyl acetate, acetonitrile, and a mixture thereof. Examples ofthe base include organic bases such as triethylamine,N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene,n-butyllithium, and the like, and inorganic bases such as sodiumcarbonate, potassium carbonate, sodium hydride, potassium tert-butoxide,and the like. It may be advantageous to carry out a reaction in thepresence of a phase transfer catalyst such as tetra-n-butylammoniumchloride and the like in some cases.

A compound of the general formula (IIIf) can be obtained by the methoddescribed in the Starting Material Synthesis 3 above and a compound ofthe general formula (IIIg) can be obtained by the method described inthe Starting Material Synthesis 4 above.

REFERENCES

-   “Organic Functional Group Preparations” written by S. R. Sandler    and W. Karo, 2^(nd) Ed., vol. 1, Academic Press Inc., 1991

“Courses in Experimental Chemistry (5^(th) Ed.)” edited by The ChemicalSociety of Japan, vol. 14 (2005) (Maruzen)

(Starting Material Synthesis 8)

(wherein R^(3b) represents C₁₋₆ alkyl which may be substituted, C₃₋₈cycloalkyl, aryl which may be substituted, or a hetero ring which may besubstituted, among the groups defined as R³. Further, among the C₁₋₆alkyl which may be substituted, one having oxo substituted on a carbonatom directly bonded to a nitrogen atom connected with R^(3b) isexcluded).

The compound of the general formula (10) can be obtained by using thecompound of the general formula (9) and a suitable aldehyde or ketonecompound in equivalent amounts, and stirring a mixture thereof under atemperature condition from −45° C. to heating and refluxing, preferablyat 0° C. to room temperature, usually for 0.1 hours to 5 days, in asolvent inert to the reaction in the presence of a reducing agent.Examples of the solvent used herein are not particularly limited, butinclude alcohols such as methanol, ethanol, and the like, ethers such asdiethylether, tetrahydrofuran, dioxane, dimethoxyethane, and the like,and a mixture thereof. Examples of the reducing agent include sodiumcyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, andthe like. It is preferable in some cases to carry out the reaction inthe presence of a dehydrating agent such as molecular sieves, and thelike or an acid such as acetic acid, hydrochloric acid, a titanium(IV)isopropoxide complex, and the like. Further, the reaction can be carriedout in a solvent such as methanol, ethanol, ethyl acetate, and the like,in the presence or absence of an acid such as acetic acid, hydrochloricacid, and the like, using a reduction catalyst (for example, palladiumon carbon, Raney nickel, and the like), instead of treatment with thereducing agent. In this case, it is preferable to carry out the reactionunder a hydrogen atmosphere from normal pressure to 50 atmospheres undera temperature condition ranging from cooling to heating.

A compound of the general formula (IIIh) can be obtained by using thecompound of the general formula (10) and a suitable halogenocarboxylicester and reacting them in the presence of a base.

The compound of the general formula (IIIi) can be obtained by using themethod described in the Starting Material Synthesis 4 above and carryingout reduction of a carbonyl group of the compound of the general formula(IIIh).

REFERENCES

-   “Comprehensive Organic Functional Group Transformations II” written    by A. R. Katritzky and R. J. K. Taylor, vol. 2, Elsevier Pergamon,    2005-   “Courses in Experimental Chemistry (5^(th) Ed.)”, edited by The    Chemical Society of Japan, vol. 14 (2005) (Maruzen)

The compounds of the formula (I) can be isolated and purified as theirfree compounds, salts, hydrates, solvates, or polymorphic crystalsubstances thereof. The salts of the compound of the formula (I) can beprepared by carrying out the treatment of a conventional salt formingreaction.

Isolation and purification are carried out by employing ordinarychemical operations such as extraction, fractional crystallization,various types of fractional chromatography, and the like.

Various isomers can be prepared by selecting an appropriate startingcompound or separated by using the difference in the physicochemicalproperties between the isomers. For example, the optical isomers can beobtained by means of a general method for designing optical resolutionof racemic products (for example, fractional crystallization forinducing diastereomer salts with optically active bases or acids,chromatography using a chiral column or the like, and others), andfurther, the isomers can also be prepared from an appropriate opticallyactive starting material.

The pharmacological activity of the compound of the formula (I) wasconfirmed by the tests shown below.

Test Example 1 Evaluation of 5-HT_(2C) Receptor Agonist Activity

The agonist activity of the compound of the formula (I) on the 5-HT_(2C)receptor was confirmed by the method shown below.

The human 5-HT_(2C) receptor agonist activity was evaluated by measuringthe increase of the ligand-dependent intracellular calciumconcentration. CHO cells which stably expressing a human 5-HT_(2C)receptor were used. The receptor-expressing cells were prepared bytransfecting the genes of the human 5-HT_(2C) receptor (Accessionnumbers: AF498983 (5-HT_(2C))) into CHO cells (dihydrofolicacid-deficient strain, DS Pharma Biomedical Co., Ltd.)) using a pEF-BOSvector (Nucleic Acids Research, vol. 18, No. 17). After transcription,the 5-HT_(2C) is known to be subjected to RNA editing to causedifferences in three kinds of amino acids, resulting in fourteenreceptor isoforms. Among them, cells stably expressing an INI type of5-HT_(2C) receptor which had not been subjected to editing were used.Cells used for evaluation were cultured in a 10% fetal bovine serum(FBS)-containing medium (trade name: α-MEM, Invitrogen) at 37° C. and 5%carbon dioxide. On the day before the evaluation, the cells weresuspended in a serum-free medium (trade name: CD-CHO, Invitrogen)containing 8 mM L-glutamine (trade name: L-glutamine 200 mM, Invitrogen,added to the medium at a final concentration of 8 mM) and dispensed intoa 96-well poly-D-lysine-coated plate (trade name: Biocoat PDL96WBlack/Clear, Japan Becton, Dickinson and Company)) at 4×10⁴ cells/welland cultured at 37° C. and 5% carbon dioxide overnight. A solutionincluding a washing solution (mixture of Hank's Balanced Salt Solution(HBSS)-sodium hydroxide (NaOH), 20 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES)-sodiumhydroxide (NaOH), 2.5 mM probenecid, and 0.1% bovine serum albumin(BSA)), and a 4 μM fluorescent reagent (trade name: Fluo-4-AM, DojindoCo., Ltd.) was used as a loading buffer and the medium of the 96-wellplate which had been cultured overnight was replaced with a loadingbuffer. After leaving to stand (with light-shielding) at roomtemperature for 3 hours, the cells were washed with a plate washer(trade name: ELx405, BioTek Instruments, Inc.) in which a washingsolution had been set up. The plates of the washed cells were set up ina system for measuring a calcium (Ca) concentration in a cell (tradename: FLIPR, Molecular Devices, Inc.). In this device, a test compoundthat had been dissolved in dimethyl sulfoxide and diluted in the washingsolution at a predetermined concentration was added and set up tomeasure a change in the Ca concentrations in a cell. The differencebetween a maximum value and a minimum value in the change of theintracellular Ca concentration was determined and kept as measurementdata.

Taking the maximum reaction of the 5-HT (agonist action with addition of5-HT 10 μM) as 100% and the reaction of a solvent alone as 0%, theefficacy (Emax (%)) and potency (EC50 (nM)) of the present inventioncompound to the maximum reaction of the 5-HT were calculated with alogistic regression method.

The results of several compounds are shown in Table 1. In the Table, Exrepresents Example Compound No. below.

TABLE 1 5-HT_(2C) agonist activity Ex EC50 (nM) Emax (%) 2 0.64 99 161.5 109 21 0.81 101 33 32.9 94 35 0.42 100 36 12 97 38 2.1 94 42 1.9 9745 3.9 107 50 68 98 56 3.2 112 58 4.0 117 59 7.1 108 76 1.9 116 78 36 9881 0.84 114 88 1.1 105 90 8.3 113 92 79 84 98 4.4 107 104 1.1 107 1058.0 111 106 1.1 112 108 5.9 106 135 2.9 112 141 0.36 100 215 1.0 96 2430.53 96 258 1.9 97 263 2.8 96 265 1.3 97 267 0.51 99 268 0.92 99 276 6.4104 277 2.3 95 283 1.7 90 287 1.0 97 288 0.64 90 290 3.8 93 291 1.2 93292 0.65 93 297 0.71 96 299 1.0 98 313 4.2 97 315 2.8 108

Test Example 2 Measurement of External Urethral SphincterElectromyography

The activating action of the compound of the formula (I) on the urethralsphincter electromyography was confirmed with the method shown below.

Hartley female guinea pigs with a body weight of 250 to 350 g wereanesthetized with urethane (Sigma). The guinea pigs were fixed in asupine position and catheters (PE-50; Clay Adams) for administration oftest compounds were inserted into the jugular vein. Further, a catheters(PE-160; Clay Adams), for an infusion of physiological saline intobladder and measurement of the intravesical pressure, were insertedthrough an incision into the dome of the bladder. Further, in order tomeasure the external urethral sphincter electromyography, two electrodeswere inserted into both the left and right sides of the urethral openingto the urethral sphincter. The electrodes for measuring base voltageswere placed under the skin of the hind part. The bladder catheter wasbranched over a three-way stopcock, and one was connected with a 50 mLsyringe (Terumo) fixed to an infusion pump (Terumo). The other wasconnected to a pressure transducer (DX-100; Nihon Kohden Corporation) totransfer the signal of the transducer through an amplifier (AP-630G;Nihon Kohden Corporation) and a data acquisition system (PowerLab; ADInstruments) to a computer and record on a hard disk. The electrodes forelectromyography measurement were connected to a control unit (JB-101J;Nihon Kohden Corporation) to transfer the signal through an amplifier(AP-651J; Nihon Kohden Corporation) and a data acquisition system(PowerLab; AD Instruments) to a computer and record on a hard disk.Further, the data were analyzed on the computer using a software (Chart;AD Instruments). Physiological saline was continuously injected into thebladder using an infusion pump at a rate of 18 mL/hour and it wasconfirmed that a micturition reflexes were stably induced. Theelectromyography activity was analyzed by taking the lowest potentialamplitude as a standard during the stabilization period and using thefiring frequency over the standard amplitude as an indicator. Atintervals between the respective urinations (urine filling phase), theactivity of the urethral sphincter electromyography was analyzed and itsaverage value was calculated. After the stabilization period, thesolvent and the test compound were administered at an increased dose atan interval of 40 minutes through the catheter placed into the jugularvein. The urethral sphincter electromyography activity after theadministration of the solvent was taken as 100% and the urethralsphincter electromyography activity after the administration of the testcompound was denoted as a percentage (%) of the electromyographyactivity after the administration of the solvent.

As a result, the compounds of Example 81, Example 59, Example 88,Example 104, Example 106, Example 141, Example 38, Example 135, Example215, Example 243, Example 265, Example 287, Example 258, Example 263,Example 267, Example 268, Example 276, Example 277, Example 283, Example288, Example 290, Example 291, Example 292, Example 297, Example 299,Example 313, and Example 315 as shown later showed an external urethralsphincter electromyography activity of 200% or more with intravenousadministration at 3 mg/kg.

As a result of each test above, it was confirmed that the compound ofthe formula (I) has a 5-HT_(2C) receptor agonist activity, and thecompound of the formula (I) can be used for treatment or prevention of5-HT_(2C) receptor-related diseases, particularly incontinence such asstress urinary incontinence, urge urinary incontinence, mixed urinaryincontinence, and the like, sexual dysfunction such as erectiledysfunction syndrome and the like, obesity, and the like as apharmaceutical.

According to the results obtained by the tests above, it is consideredthat the compound has a 5-HT_(2C) receptor agonist activity and thus hassubstantially the same or a higher activity value than Lorcaserin underdevelopment as an anti-obesity drug (The Journal of Pharmacology andExperimental Therapeutics vol. 325, No. 2 p. 577-587 (2008)).

A pharmaceutical composition containing one or two or more kinds of thecompound of the formula (I) or a salt thereof as an active ingredientcan be prepared using excipients that are usually used in the art, thatis, excipients for pharmaceutical preparation, carriers forpharmaceutical preparation, and the like according to the methodsusually used.

Administration can be accomplished either by oral administration viatablets, pills, capsules, granules, powders, solutions, and the like, orparenteral administration injections, such as intraarticular,intravenous, or intramuscular injections, and the like, suppositories,ophthalmic solutions, eye ointments, transdermal liquid preparations,ointments, transdermal patches, transmucosal liquid preparations,transmucosal patches, inhalations, and the like.

The solid composition for oral administration is used in the form oftablets, powders, granules, or the like. In such a solid composition,one or more active ingredient(s) are mixed with at least one inactiveexcipient. According to a usual method, the composition may containinactive additives, such as lubricants, disintegrating agents,stabilizing agents, and solubilization assisting agents. If necessary,tablets or pills may be coated with sugar or a film of a gastric orenteric coating substance.

The liquid composition for oral administration contains pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, or thelike, and also contains generally used inert diluents, for example,purified water or ethanol. In addition to the inert diluent, the liquidcomposition may also contain auxiliary agents, such as a solubilizationassisting agent, a moistening agent, and a suspending agent, as well assweeteners, flavors, aromatics, and antiseptics.

The injections for parenteral administration contain sterile aqueous ornon-aqueous solutions, suspensions, or emulsions. Examples of theaqueous solvent include distilled water for injection use andphysiological saline. Examples of the non-aqueous solvent includealcohols such as ethanol. Such a composition may further contain atonicity agent, an antiseptic, a moistening agent, an emulsifying agent,a dispersing agent, a stabilizing agent, and a solubilization assistingagent. These are sterilized by filtration through a bacteria retainingfilter, blending of a germicide, or irradiation. Furthermore, they mayalso be prepared in the form of sterile solid compositions and dissolvedor suspended in sterile water or a sterile solvent for injecting priorto their use.

Examples of the formulation for external use include ointments,plasters, creams, jellies, patches, sprays, lotions, eye-drops, eyeointments, and the like. The drug contains generally used ointmentbases, lotion bases, aqueous or non-aqueous liquid preparations,suspensions, emulsions, or the like.

Transmucosal agents such as inhalers, transnasal agents, and the likeare used in the form of solids, liquids, or semisolids and can beprepared according to conventional known methods. For example, knownexcipients, and further, pH adjusters, antiseptics, surfactants,lubricants, stabilizing agents, thickeners, or the like may also beadded where appropriate. For administration, suitable devices forinhalation or insufflation can be used. For example, using known devicesand sprayers such as a metered dose inhaler, the compound can beadministered independently or in the form of prescribed mixture powders.Furthermore, the compound combined with pharmaceutically acceptablecarriers can also be administered in the form of solutions orsuspensions. Dry powder inhalers and the like may be devices for singleor multiple administrations, and dry powders or capsules containingpowders can also be used. Still further, the devices may be in the formof a pressure aerosol spray or the like that use suitable ejectionagents, for example, chlorofluoroalkane, hydrofluoroalkane, or asuitable gas such as carbon dioxide and the like.

Usually, in the case of oral administration, the daily dose is suitablyfrom 0.001 to 100 mg/kg per body weight, preferably from 0.1 to 30mg/kg, and more preferably from 0.1 to 10 mg/kg, and this isadministered in one portion or dividing it into 2 to 4 portions. In thecase of intravenous administration, the daily dose is suitably fromabout 0.0001 to 10 mg/kg per body weight, and this is administered oncea day or two or more times a day. In addition, a transmucosal agent isadministered at a dose from about 0.001 to 100 mg/kg per body weight,and this is administered once a day or two or more times a day. The doseis appropriately decided in response to an individual case by taking thesymptoms, the age, the gender, and the like into consideration.

Although varying depending on administration routes, dosage forms,administration sites, or the types of excipients and additives, thepharmaceutical composition of the present invention contains 0.01 to100% by weight, and in a certain embodiment, 0.01 to 50% by weight ofone or more kinds of the compound of the formula (I) or a salt thereof,which is an active ingredient.

The compound of the formula (I) can be used in combination with variousagents for treating or preventing the diseases, in which the compound ofthe formula (I) is considered effective, as described above. Thecombined preparation may be administered simultaneously or separatelyand continuously, or at a desired time interval. The preparations to beco-administered may be prepared individually or may be a pharmaceuticalcomposition including various agents for treating or preventing thediseases, in which the compound of the formula (I) is consideredeffective, as described above, and the compound of the formula (I).

EXAMPLES

Hereinbelow, the preparation methods for the compound of the formula (I)and the starting compounds thereof will be described in more detail withreference to Examples. The present invention is not limited to thecompounds described in the Examples described below. Furthermore, theproduction processes for the starting compounds will be described inPreparation Examples. The preparation methods for the compound of theformula (I) are not limited to the preparation methods of the specificExamples as below, but the compound of the formula (I) can be preparedby any combination of the preparation methods or the methods that areapparent to a person skilled in the art.

Furthermore, the following abbreviations may be used in some cases inthe Preparation Examples, Examples, and Tables below.

PEx: Preparation Example No., Ex: Example No., PSyn: Preparation ExampleNo. prepared by the same method, Syn: Example No. prepared by the samemethod, No: Compound No., Str: Structural formula, Dat: PhysicochemicalData, EI: m/z values in mass spectroscopy (Ionization EI, representing(M)⁺ unless otherwise specified), ESI+: m/z values in mass spectroscopy(Ionization ESI, representing (M+H)⁺ unless otherwise specified), ESI−:m/z values in mass spectroscopy (Ionization ESI, representing (M−H)⁻unless otherwise specified), FAB+: m/z values in mass spectroscopy(Ionization FAB, representing (M+H)⁺ unless otherwise specified), FAB−:m/z values in mass spectroscopy (Ionization FAB, representing (M−H)⁻unless otherwise specified), APCI+: m/z values in mass spectroscopy(Ionization APCI, representing (M+H)⁺ unless otherwise specified), NMR:δ (ppm) in ¹H NMR in DMSO-d₆, NMR-A: δ (ppm) in ¹H NMR in DMSO-d₆ (withaddition of trifluoroacetic acid), NMR-C: δ (ppm) in ¹H NMR in CDCl₃, s:singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), q:quartet (spectrum), br: broad line (spectrum) (e.g.: br-s), mp: meltingpoint (° C.).

Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, nBu: normalbutyl, iBu: isobutyl, t-Bu: tert-butyl, cPr: cyclopropyl, cBu:cyclobutyl, cPen: cyclopentyl, cHex: cyclohexyl, Bz: benzyl, Boc:t-butoxycarbonyl, MeOH: methanol, EtOH: ethanol, EtOAc: ethyl acetate,HEX: n-hexane, DMF: N,N-dimethylformamide, TFA: trifluoroacetic acid,THF: tetrahydrofuran, DPPA: diphenylphosphorylazide, HOBt:1-hydroxybenzotriazole.

HCl in the structural formula indicates that the Example compound isisolated as a hydrochloride. Further, a case where the structuralformula of fumaric acid is described together in the structural formulaindicates that the Example compound is isolated as fumarate. Also, acase where the structural formula of oxalic acid is described togetherin the structural formula indicates that the Example compound isisolated as an oxalate. In addition, a case where the structural formulaof succinic acid is described together in the structural formulaindicates that the Example compound is isolated as a succinate.

Furthermore, in the case where a numeral is prefixed to HCl, the numeralmeans a molar ratio of the compound to hydrochloric acid. For example,2HCl represents dihydrochloride. Further, in the Example Compounds inwhich the structural formula of fumaric acid is described together inthe structural formula, “M” described under the Example No. indicatesthat the Example Compound is isolated as monofumarate, “H” described assuch indicates that the Example Compound is isolated as hemifumarate,and “S” described as such indicates that the Example Compound isisolated as sesquifumarate. Also, “T” of Example 267 indicates that thecompound is isolated as 0.75 fumarate. Further, description of these“M”, “H”, and “S” has the same meanings in the Example Compound in whichthe structural formula of oxalic acid is described together in thestructural formula and the Example Compound in which where thestructural formula of succinic acid is described together in thestructural formula.

Furthermore, for the sake of convenience, a concentration mol/l isexpressed as M. For example, a 1 M aqueous sodium hydroxide solutionmeans a 1 mol/l aqueous sodium hydroxide solution.

Preparation Example 1

To a solution of 27.11 g of 3-chloro-o-xylene in 300 ml of carbontetrachloride were added 75 g of N-bromosuccinimide and 0.81 g of2,2′-azobis(isobutyronitrile), followed by heating and refluxing for 2hours. The reaction mixture was washed with water and saturated sodiumhydrogen carbonate, the organic layer was dried over anhydrous magnesiumsulfate and then filtered, and the filtrate was concentrated underreduced pressure to obtain 63.297 g of1,2-bis(bromomethyl)-3-chlorobenzene as a reddish orange oily substance.

Preparation Example 2

To a solution of 20.5 g of sodium cyanide in 120 ml of water was added asolution of 57.533 g of 1,2-bis(bromomethyl)-3-chlorobenzene in 120 mlof EtOH, followed by heating and refluxing for 30 minutes. The reactionmixture was poured into ice, followed by stirring, and the precipitatedsolid was collected by filtration to obtain 32.941 g of2,2′-(3-chloro-1,2-phenylene)diacetonitrile as a yellowish brown solid.

Preparation Example 3

To a suspension of 32.94 g of2,2′-(3-chloro-1,2-phenylene)diacetonitrile in 100 ml of acetic acid wasadded dropwise 100 ml of a 33% hydrogen bromide-acetic acid solutionover 1.5 hours while keeping the inner temperature at 20° C. or lower.The reaction mixture was stirred at room temperature for 3 hours, andthen to the reaction mixture were added diethylether and acetone. Theresulting candy-like dark brown solid substance and the suspension wereseparated, the suspension was concentrated under reduced pressure, andthe candy-like substance was pulverized in acetone to obtain asuspension. The concentrated residue and the acetone suspension werecombined and concentrated under reduced pressure, and to the residue wasadded EtOAc, followed by stirring. The solid was collected byfiltration. The resulting solid was suspended in 400 ml of water whichhad been heated to 80° C., and 31.2 g of sodium acetate was addedthereto, followed by stirring at 90° C. for 3 hours. The reactionmixture was cooled to room temperature and then the solid was collectedby filtration to obtain 22.506 g of6-chloro-1H-3-benzazepine-2,4(3H,5H)-dione as a brown solid.

Preparation Example 4

To a solution of 22.5 g of 6-chloro-1H-3-benzazepine-2,4(3H,5H)-dione in200 ml of THF were added dropwise 38 ml of a 10 M borane-dimethylsulfide complex at 0° C. for 20 minutes, followed by stirring for 2.5hours. The reaction mixture was heated and refluxed, and furtherstirred. To the reaction mixture was added dropwise 30 ml of MeOH underice-cooling, followed by stirring, and then 30 ml of 4 M hydrochloricacid was added dropwise thereto, followed by heating and refluxing for 1hour after generation of bubbles substantially settled. The mixture wasalkalified by the addition of aqueous ammonia and a 1 M aqueous sodiumhydroxide solution, followed by extraction with chloroform. The organiclayer was dried over anhydrous sodium sulfate and then filtered. Thefiltrate was concentrated under reduced pressure, the residue wasdissolved in EtOH, and activated carbon was added thereto, followed byheating and refluxing, and then filtering on amino silica gel, and thefiltrate was concentrated under reduced pressure. To a solution of 18.7g of the resulting residue in 180 ml of dichloromethane was added 17 mlof pyridine, followed by ice-cooling, and 13 ml of ethyl chlorocarbonatewas added dropwise thereto, followed by stirring for 1.5 hours. Thereaction mixture was concentrated under reduced pressure, the residuewas diluted with EtOAc, then washed with 1 M hydrochloric acid andwater, dried over anhydrous sodium sulfate, and then filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 9.653 g of ethyl6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a reddishbrown oily substance.

Preparation Example 5

A solution of 11.86 g of ethyl6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 30 ml ofchloroform was ice-cooled, and while maintaining the inner temperatureat 10° C. or lower, 60 ml of concentrated sulfuric acid was addedthereto. Then, 3.2 ml of concentrated nitric acid was added dropwisethereto, followed by stirring for 30 minutes. The reaction mixture waspoured into ice, followed by extraction with chloroform, the organiclayer was dried over anhydrous sodium sulfate and then filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 6.442 g of ethyl6-chloro-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as areddish orange viscous substance and 5.201 g of ethyl6-chloro-9-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as apale yellow solid.

Preparation Example 6

To 6.431 g of ethyl6-chloro-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate wasadded 120 ml of EtOH, followed by stirring at 60° C. for dissolution,and 12.15 g of reduced iron and 60 ml of 1 M hydrochloric acid wereadded thereto, followed by heating and refluxing for 1 hour. Thereaction mixture was alkalified by the addition of a 1 M aqueous sodiumhydroxide solution and then filtered through celite, and then theorganic solvent was evaporated under reduced pressure. The residue wasextracted with chloroform, the organic layer was dried over anhydroussodium sulfate and then filtered, and the filtrate was concentratedunder reduced pressure to obtain 5.743 g of ethyl7-amino-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as areddish orange viscous substance.

Preparation Example 7

To a solution of 5.74 g of ethyl7-amino-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in100 ml of dichloromethane was added portionwise 3.9 g ofN-bromosuccinimide under ice-cooling, followed by stirring for 40minutes. The reaction mixture was concentrated under reduced pressureand the residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 5.769 g of ethyl7-amino-8-bromo-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateas a brown solid.

Preparation Example 8

To a solution of 4.37 g of ethyl7-amino-8-bromo-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 40 ml of DMF were added 2.1 ml of ethyl acrylate, 230 mg oftris-o-tolylphosphine, 85 mg of palladium(II) acetate, and 3.6 ml oftriethylamine, followed by stirring at 120° C. for 3 hours. The reactionmixture was diluted with EtOAc, washed with water and saturated brine,dried over anhydrous sodium sulfate, and then filtered, and the filtratewas concentrated under reduced pressure. The resulting yellow solid wasstirred and washed in diisopropylether to obtain 3.125 g of ethyl7-amino-6-chloro-8-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateas a pale yellow solid.

Preparation Example 9

To a solution of 2.12 g of ethyl7-amino-6-chloro-8-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 20 ml of chloroform and 20 ml of MeOH was added 65 mg of platinum(IV)oxide, followed by stirring for 20 hours at 1 atm under a hydrogenatmosphere. The reaction mixture was filtered through celite and thefiltrate was concentrated under reduced pressure to obtain 2.256 g ofethyl11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a milky white solid.

Preparation Example 10

To a suspension of 1.403 g of11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one in15 ml of dioxane were added 1.2 ml of triethylamine and 1.5 g ofdi-t-butyl dicarbonate, followed by stirring at room temperature for 2hours. The reaction mixture was concentrated under reduced pressure andthe residue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 1.779 g of t-butyl11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a milky white solid.

Preparation Example 11

To a solution of 1.772 g of t-butyl11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 10 ml of THF was added 10.1 ml of a 1 M solution of a borane-THFcomplex in THF under ice-cooling, followed by elevating to roomtemperature and stirring for 3 hours. To the reaction mixture was addeddropwise 10 ml of EtOH, and subsequently 10 ml of a 1 M aqueous sodiumhydroxide solution was added dropwise thereto, followed by stirring. Themixed solution was diluted with water, followed by extraction withEtOAc. The organic layer was dried over anhydrous sodium sulfate andthen filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 2.007 g of t-butyl11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless viscous substance.

Preparation Example 12

To a solution of 205 mg of t-butyl11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 3 ml of acetonitrile were added 0.077 ml of 36% formalin, 58 mg ofsodium cyanoborohydride, and 0.5 ml of acetic acid, followed by stirringat room temperature. To the reaction mixture was added water, followedby extraction with EtOAc, the organic layer was dried over anhydroussodium sulfate and then filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 96 mg of t-butyl11-chloro-1-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas an orange viscous substance.

Preparation Example 13

To a solution of 193 mg of t-butyl11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 2 ml of toluene was added 0.121 ml of isobutyric chloride, followedby stirring at 60° C. The reaction mixture was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 80 mg of t-butyl11-chloro-1-isobutyryl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless solid.

Preparation Example 14

To a solution of 1.75 g of 2,3,4,5-tetrahydro-1H-3-benzazepine in 20 mlof dichloromethane was added 2.884 ml of pyridine. The reaction mixturewas ice-cooled, and 1.705 ml of ethyl chloroformate which had beendissolved in 5 ml of dichloromethane was added dropwise thereto,followed by stirring overnight. The reaction mixture was concentratedunder reduced pressure and the residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 2.15 g of ethyl1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow oilysubstance.

Preparation Example 15

287 mg of ethyl2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatewas dissolved in 5 ml of DMF, and 65 mg of 60% sodium hydride was addedthereto in an ice-bath, followed by stirring for 1 hour. 0.3 ml ofmethyl iodide was added thereto, followed by stirring at roomtemperature for 3 hours. Then, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction withchloroform. The solvent was concentrated under reduced pressure and theresidue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 94 mg of ethyl1-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless solid.

Preparation Example 71

To 5 g of ethyl2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatewere added 40 ml of ethylene glycol and 28 ml of a 4 M aqueous sodiumhydroxide solution, followed by stirring at 150° C. After stirringovernight, the reaction mixture was ice-cooled, then acidified by theaddition of concentrated hydrochloric acid, and stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and then the residue was alkalified by the addition ofa 1 M aqueous sodium hydroxide solution, followed by extraction withchloroform. The solvent was concentrated under reduced pressure and thenthe resulting dark brown residue was dissolved in dichloromethane,followed by addition of 4 g of di-t-butyl dicarbonate and 3.5 ml oftriethylamine. The reaction mixture was stirred at room temperatureovernight and concentrated under reduced pressure, and the residue waspurified by silica gel chromatography (elution solvent: chloroform-MeOH)to obtain 3.39 g of t-butyl2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.

Preparation Example 17

To a solution of 250 mg of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in2.5 ml of dichloroethane were added 0.175 ml of isobutyryl chloride and0.4 ml of triethylamine, followed by elevating the temperature to 60° C.and stirring for 30 minutes. The reaction mixture was diluted with EtOAcand washed with 1 M hydrochloric acid, water, a 1 M aqueous sodiumhydroxide solution, and saturated brine, and the solvent wasconcentrated. To the resulting residue was added 2 ml of THF and 3.5 mlof a 1 M solution of a borane-THF complex in THF was added thereto in anice-bath, followed by stirring at room temperature overnight. Thereaction mixture was ice-cooled, and EtOH was added thereto, followed bystirring at room temperature for 30 minutes. The reaction mixture wasconcentrated and the resulting residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 213 mg of t-butyl1-isobutyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.

Preparation Example 18

To a solution of 460 mg of t-butyl11-bromo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 9 ml of dioxane were added 1.6 ml of a 2 M aqueous potassiumcarbonate solution under an argon atmosphere, and subsequently 449 mg oftrimethylboroxine and 70 mg of tetrakistriphenylphosphine palladium,followed by stirring at 90° C. for 13 hours. The reaction mixture wasallowed to cool, filtered, and then concentrated under reduced pressure,the resulting residue was diluted with EtOAc, and the organic layer waswashed with water and saturated brine. The solvent was evaporated underreduced pressure and the resulting residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 380 mg of t-butyl11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.

Preparation Example 19

To a solution of 670 mg of t-butyl11-isopropenyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 10 ml of MeOH was added 200 mg of palladium on carbon, followed bystirring at room temperature for 3.5 hours at normal pressure under ahydrogen atmosphere. Further, after stirring overnight at 4.5 atm undera hydrogen atmosphere, the reaction mixture was filtered through celite,and the solvent was evaporated under reduced pressure. The resultingresidue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 512 mg of t-butyl11-isopropyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.

Preparation Example 20

To a solution of 140 mg of t-butyl11-ethyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 1.86 ml of acetonitrile was added 0.12 ml of glycidylmethylether,followed by substitution with argon. In an ice-bath, 9 mg ofytterbium(III) trifluoromethanesulfonate was added thereto, followed bystirring at room temperature for 2 hours, then elevating the temperatureto 50° C., and stirring overnight. To the reaction mixture were addedEtOAc and aqueous sodium bicarbonate, and the organic layer was washedwith water and saturated brine. The solvent was evaporated under reducedpressure and the resulting residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 147 mg of t-butyl11-ethyl-1-(2-hydroxy-3-methoxypropyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.

Preparation Example 21

To a solution of 215 mg of t-butyl7-hydroxy-8-(tetrahydro-2H-pyran-4-ylamino)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 4 ml of DMF were added 98 mg of potassium carbonate and 0.062 ml ofmethyl bromoacetate, followed by stirring at room temperature for 6hours. To the reaction mixture was added water, followed by extractionwith EtOAc twice. The combined organic layer was washed with saturatedbrine three times, dried over anhydrous sodium sulfate, and thenfiltered, and the solvent was evaporated under reduced pressure. To asolution of 259 mg of the resulting residue in 7 ml of EtOH was added1.2 ml of a 1 M aqueous sodium hydroxide solution, followed by stirringat 50° C. overnight. Further, 1.2 ml of a 1 M aqueous hydrochloric acidsolution was added thereto under ice-cooling, followed by extractionwith chloroform twice, and the combined organic layer was dried overanhydrous sodium sulfate and then filtered. The solvent was evaporatedunder reduced pressure. To a solution of 239 mg of the resulting residuein 4 ml of DMF were added 120 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 84 mg ofHOBt at room temperature, followed by stirring at room temperatureovernight. Water was added thereto, followed by extraction with EtOActwice. The combined organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and then filtered, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography (elution solvent: HEX-EtOAc) to obtain 153 mg oft-butyl3-oxo-4-(tetrahydro-2H-pyran-4-yl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a white solid.

Preparation Example 22

To a solution of 828 mg of t-butyl7-hydroxy-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 25 ml of DMF were added 0.268 ml of methyl bromoacetate and 390 mg ofpotassium carbonate, followed by stirring at 55° C. for 13 hours. Thereaction mixture was allowed to cool, and water added, followed byextraction with EtOAc twice. The combined organic layer was washed withsaturated brine, the organic layer was dried over anhydrous sodiumsulfate and then filtered, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 1.076 g of t-butyl7-(2-methoxy-2-oxoethoxy)-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateas a yellowish white solid.

Preparation Example 23

To a mixture of 967 mg of t-butyl7-(2-methoxy-2-oxoethoxy)-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 25 ml of EtOH was added 97 mg of 10% palladium on carbon under anargon atmosphere, followed by stirring for 2 hours at normal pressureunder a hydrogen atmosphere. To the reaction mixture was added 200 ml ofTHF, then the catalyst was removed using celite, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography (elution solvent: HEX-EtOAc) to obtain 629 mg oft-butyl11-methyl-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a white solid.

Preparation Example 24

To a solution of 120 mg of t-butyl2-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 4 ml of DMF were added 0.026 ml of methyl iodide and 104 mg ofpotassium carbonate at room temperature, followed by stirring for 13hours. To the reaction mixture were added 0.012 ml of methyl iodide and26 mg of potassium carbonate, followed by further stirring for 3 hours.To the reaction mixture was added water, followed by extraction withEtOAc twice. The combined organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, and then filtered, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography (elution solvent: HEX-EtOAc) to obtain 55 mgof t-butyl2,4-dimethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a brown solid.

Preparation Example 25

To a solution of 120 mg of t-butyl2-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 4 ml of DMF were added 0.113 ml of isopropyl iodide and 0.197 ml ofdiisopropylethylamine, followed by stirring at 100° C. for 6.5 hours.Further, to the reaction mixture were added 0.113 ml of isopropyl iodideand 0.197 ml of diisopropylethylamine, followed by stirring at 100° C.for 4 hours. Further, to the reaction mixture were added 0.226 ml ofisopropyl iodide and 0.394 ml of diisopropylethylamine, followed bystirring at 100° C. for 19 hours. The reaction mixture was cooled toroom temperature, and water added, followed by extraction with EtOActwice. The combined organic layer was washed with saturated brine, theorganic layer was dried over anhydrous sodium sulfate and then filtered,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 90 mg of t-butyl4-isopropyl-2-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(211)-carboxylateas a pale brown solid.

Preparation Example 26

To a solution of 130 mg of t-butyl3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 4 ml of dichloromethane were added 0.036 ml of methanesulfonylchloride and 0.089 ml of diisopropylethylamine under ice-cooling,followed by stirring at room temperature for 16 hours. To the reactionmixture were added 0.036 ml of methanesulfonyl chloride and 0.089 ml ofdiisopropylethylamine, followed by stirring at room temperature foradditional 9 hours. To the reaction mixture was added water, followed byextraction with chloroform. The organic layer was dried over anhydroussodium sulfate and then filtered, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatography(elution solvent: HEX-EtOAc) to obtain 152 mg of t-butyl4-(methylsulfonyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a colorless solid.

Preparation Example 27

To a mixture of 5 g of sodium borohydride and 30 ml of anhydrous THF wasadded a solution of 10.27 g of 2-methyl-3-nitrophenylacetic acid in 60ml of anhydrous THF under ice-cooling, and then a solution of 3.5 ml ofmethanesulfonic acid in 10 ml of anhydrous THF was added dropwisethereto. The reaction mixture was heated to 70° C. and then stirred for30 minutes, and 80 ml of 3 M hydrochloric acid was then added theretounder ice-cooling, followed by stirring. The mixed liquid was extractedwith chloroform, and the organic layer was dried over anhydrousmagnesium sulfate and then filtered. The filtrate was concentrated underreduced pressure to obtain 9.701 g of an orange viscous substance. To asolution of 9.53 g of the resulting substance in 100 ml ofdichloromethane were added dropwise 22 ml of diisopropylethylamine and4.75 ml of chloromethylmethylether under ice-cooling, followed bystirring for 24 hours. 1.0 ml of chloromethylmethylether was addedthereto, followed by further stirring for 24 hours. The reaction mixturewas concentrated under reduced pressure and the residue was purified bysilica gel chromatography (elution solvent: HEX-EtOAc) to obtain 11.26 gof a yellow oily substance. To a solution of 11.26 g of the resultingsubstance in 200 ml of EtOH was added 340 mg of platinum(IV) dioxide,followed by stirring at room temperature for 1 hour under a hydrogenatmosphere of 4 atm. The reaction mixture was removed using celite andthe filtrate was concentrated under reduced pressure to obtain 9.21 g ofan orange viscous substance. To a solution of the residue in 200 ml ofdichloromethane and 40 ml of MeOH were added 14.2 g of calcium carbonateand 36.5 g of benzyl trimethylammonium dichloroiodate, followed bystirring at room temperature for 13 hours. The insoluble materials wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 15.93 g of4,6-diiodo-3-[2-(methoxymethoxy)ethyl]-2-methylaniline as a dark redviscous substance.

Preparation Example 28

To a mixed liquid of 400 mg of palladium(II) acetate, 934 mg oftriphenylphosphine, 9.91 g of tetrabutylammonium chloride, and 7 g ofpotassium acetate in 150 ml of DMF was added a solution of 15.93 g of4,6-diiodo-3-[2-(methoxymethoxy)ethyl]-2-methylaniline in 150 ml of DMF,and 16 ml of ethyl acrylate was added thereto, followed by stirring at80° C. for 3 hours. The reaction mixture was diluted with EtOAc, washedwith water and saturated brine, and concentrated under reduced pressure.The residue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 12.11 g of a yellow solid. To a solution of 12.11 gof the resulting substance in 250 ml of EtOH and 250 ml of THF was added701 mg of platinum(IV) oxide, followed by stirring at room temperaturefor 4 hours under a hydrogen atmosphere of 4 atm. The reaction mixturewas removed using celite and the filtrate was concentrated-under reducedpressure to obtain 11.39 g of ethyl3-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}propanoateas a milky white solid.

Preparation Example 29

To a solution of 10.81 g of ethyl3-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}propanoatein 100 ml of EtOH and 100 ml of THF was added 100 ml of a 1 M aqueoussodium hydroxide solution, followed by stirring at room temperature for1 hour. The reaction mixture was neutralized by the addition ofhydrochloric acid and then concentrated under reduced pressure to onethird of the liquid amount, and the residue was extracted withchloroform. The organic layer was dried over anhydrous magnesium sulfateand then filtered, and the filtrate was concentrated under reducedpressure. To a solution of the resulting residue in 300 ml of t-butanolwere added 9.0 ml of triethylamine and 7.0 ml of DPPA, followed byheating and refluxing for 24 hours. The reaction mixture wasconcentrated under reduced pressure, the residue was purified by silicagel chromatography (elution solvent: HEX-EtOAc), and then the resultingsolid was washed with HEX to obtain 8.006 g of t-butyl(2-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}ethyl)carbamateas a milky white solid.

Preparation Example 30

To a suspension of 1.01 g of t-butyl(2-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}ethyl)carbamatein 10 ml of THF was added 10 ml of 6 M hydrochloric acid, followed bystirring at 50° C. for 1 hour. The reaction mixture was alkalified bythe addition of sodium hydroxide and then 675 mg of di-t-butyldicarbonate was added thereto, followed by stirring at room temperaturefor 15 hours. The reaction mixture was extracted with chloroform, andthe organic layer was dried over anhydrous magnesium sulfate and thenfiltered. The filtrate was concentrated under reduced pressure to obtain1.105 g of t-butyl{2-[7-(2-hydroxyethyl)-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]ethyl}carbamateas a white foamed substance.

Preparation Example 31

To a solution of 1.793 g of t-butyl{2-[7-(2-hydroxyethyl)-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]ethyl}carbamatein 30 ml of THF were added 0.48 ml of methanesulfonyl chloride and 1.5ml of triethylamine under ice-cooling, followed by stirring for 30minutes. To the reaction mixture was added portionwise 1.8 g ofpotassium t-butoxide under ice-cooling, followed by stirring for 1.5hours. To the reaction mixture was added a saturated aqueous ammoniumchloride solution, followed by extraction with EtOAc. The organic layerwas dried over anhydrous magnesium sulfate and then filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 1.06 g of t-butyl11-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a white foamed substance.

Preparation Example 32

To a solution of 167 mg of t-butyl11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 2 ml of dichloromethane were added 0.221 ml of triethylamine and0.062 ml of ethyl isocyanate, followed by stirring at room temperaturefor 15 hours. To the reaction mixture were added 3 ml of toluene and0.062 ml of ethyl isocyanate, followed by heating to 60° C. and stirringfor 15 hours. Then, the reaction mixture was concentrated under reducedpressure and the residue was purified by silica gel chromatography(elution solvent: HEX-EtOAc) to obtain 200 mg of t-butyl1-(ethylcarbamoyl)-11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless viscous substance.

Preparation Example 33

To a solution of 201 mg of t-butyl11-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 2 ml of pyridine was added 0.1 ml of ethyl chloroformate, followed bystirring at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (elution solvent: HEX-EtOAc) to obtain 261 mgof 8-t-butyl 1-ethyl11-methyl-3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylateas a colorless viscous substance.

Preparation Example 34

To a suspension of 2 g of3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propionic acid in 40 ml oft-butanol were added 2.1 ml of DPPA and 2.6 ml of triethylamine,followed by heating and refluxing at 100° C. for 18 hours. The reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel chromatography (elution solvent: chloroform-MeOH)to obtain 1.832 g oft-butyl[2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate as anorange solid.

Preparation Example 35

To a mixed solution of 770 mg oft-butyl[2-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate in 15 ml ofdichloromethane and 3 ml of MeOH were added 420 mg of calcium carbonateand 970 mg of benzyltrimethylammonium dichloroiodate, followed bystirring at room temperature for 2 hours. The insoluble materials wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 595 mg of t-butyl[2-(6-iodo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate as a reddishbrown viscous substance.

Preparation Example 36

To a solution of 595 mg oft-butyl[2-(6-iodo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate in 3ml of dichloromethane were added 3 ml of water and 376 mg of sodiumhydrogen carbonate, and a solution of 0.273 ml of benzyl chloroformatein 3 ml of dichloromethane wad added dropwise under ice-cooling whilestirring, followed by stirring for additional 5 hours. The reactionmixture was extracted with EtOAc, the organic layer was dried overanhydrous magnesium sulfate and then filtered, and the filtrate wasconcentrated under reduced pressure to obtain 877 mg of benzyl7-{2-[(t-butoxycarbonyl)amino]ethyl}-6-iodo-3,4-dihydroquirolin-1(2H)-carboxylateas a reddish orange solid.

Preparation Example 37

To a solution of 793 mg of benzyl7-{2-[(t-butoxycarbonyl)amino]ethyl}-6-iodo-3,4-dihydroquirolin-1(2H)-carboxylatein 10 ml of THF was added dropwise 1.8 ml of a 1 M solution of sodiumbistrimethylsilylamide in THF under ice-cooling, followed by stirringfor 5 minutes. Then, 0.166 ml of allyl bromide was added thereto,followed by stirring for 18 hours while slowly elevating the temperatureto room temperature. To the reaction mixture were added a saturatedaqueous ammonium chloride solution and water, followed by extractionwith EtOAc, the organic layer was dried over anhydrous magnesium sulfateand then filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 788 mg of benzyl7-{2-[allyl(t-butoxycarbonyl)amino]ethyl}-6-iodo-3,4-dihydroquirolin-1(2H)-carboxylate.

Preparation Example 38

To a mixture of 403 mg of potassium acetate, 441 mg oftetrabutylammonium bromide, 9 mg of triphenylphosphine, and 4 mg ofpalladium(II) acetate was added a solution of 788 mg of benzyl7-{2-[allyl(t-butoxycarbonyl)amino]ethyl}-6-iodo-3,4-dihydroquirolin-1(2H)-carboxylatein 25 ml of DMF, followed by substitution with argon and stirring at 80°C. for 4 hours. The reaction mixture was diluted with EtOAc, washed withwater and saturated brine, and concentrated under reduced pressure. To25 ml of a solution of the resulting residue in MeOH was added 36 mg ofplatinum(IV) oxide, followed by stirring at room temperature overnightunder a hydrogen atmosphere of 4 atm. The reaction mixture was filteredthrough celite and the filtrate was concentrated under reduced pressureto obtain 570 mg of 1-benzyl 8-t-butyl6-methyl-3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylateas an orange foamed substance.

Preparation Example 39

To a mixed liquid of 9.3 g of aluminum chloride in 30 ml ofdichloromethane was added dropwise 1.6 ml of acetyl chloride underice-cooling, followed by stirring. Then, a solution of 5 g of7-methoxy-1-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepinein 70 ml of dichloromethane was added thereto, followed by stirring for13 hours while slowly elevating the temperature to room temperature. Thereaction mixture was ice-cooled, and 30 ml of 1 M hydrochloric acid wasadded dropwise thereto, followed by addition of water and extractionwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate and then filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography(elution solvent: HEX-EtOAc) to obtain 5.137 g of1-[8-hydroxy-5-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]ethanoneas a pale brown solid.

Preparation Example 40

To a suspension of 5.13 g of1-[8-hydroxy-5-methyl-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-yl]ethanonein 50 ml of MeOH was added 50 ml of a 1 M aqueous sodium hydroxidesolution, followed by stirring at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure to a half ofthe amount, and to the residue were added 50 ml of dioxane and 4.27 g ofdi-t-butyl dicarbonate, followed by stirring at room temperature for 30minutes. The reaction mixture was neutralized by the addition of 1 Mhydrochloric acid and extracted with chloroform. The organic layer wasdried over anhydrous magnesium sulfate and then filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 4.385 g of t-butyl8-acetyl-7-hydroxy-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateas a yellow viscous substance.

Preparation Example 41

To a solution of 1.715 g of t-butyl8-acetyl-7-(2-ethoxy-2-oxoethoxy)-1-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 20 ml of EtOH was added 325 mg of hydroxylamine hydrochloride,followed by heating and refluxing for 3 hours. 500 mg of hydroxylaminehydrochloride was added thereto, followed by further heating andrefluxing for 2 hours. The reaction mixture was concentrated underreduced pressure, and to the residue was added water, followed byextraction with chloroform. The organic layer was dried over anhydroussodium sulfate and then filtered, and the filtrate was concentratedunder reduced pressure. To 10 ml of a solution of the resulting residuein acetonitrile were added 24 mg of cyanuric chloride and 33 mg ofzinc(II) chloride, followed by heating and refluxing for 12 hours. Thereaction mixture was concentrated under reduced pressure. To theresulting residue were added 10 ml of dioxane, 10 ml of a 1 M aqueoussodium hydroxide solution and 1.2 g of di-t-butyl dicarbonate, followedby stirring at room temperature for 24 hours. The reaction mixture wasconcentrated under reduced pressure to a half of the amount, made weaklyacidic by the addition of 1 M hydrochloric acid, and extracted withchloroform. The organic layer was dried over anhydrous magnesium sulfateand then filtered, and the filtrate was concentrated under reducedpressure. To the resulting residue was added 60 ml of a 17% aqueoussulfuric acid solution, followed by stirring at 100° C. for 1 hour. Thereaction mixture was ice-cooled and alkalified by the addition of 15 gof sodium hydroxide, and 50 ml of dioxane and 1.21 g of di-t-butyldicarbonate were added thereto, followed by stirring at room temperaturefor 3 hours. The reaction mixture was diluted with water and extractedwith EtOAc. The organic layer was dried over anhydrous magnesium sulfateand then filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 735 mg of t-butyl6-methyl-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2′-1)-carboxylateas a pale yellow solid.

Preparation Example 42

To a solution of 704 mg of t-butyl6-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 15 ml of dichloromethane was added portionwise 438 mg ofN-bromosuccinimide under ice-cooling, followed by stirring for 30minutes. The reaction mixture was concentrated under reduced pressureand the residue was purified by silica gel chromatography (elutionsolvent: HEX-EtOAc) to obtain 446 mg of a pale yellow foamed substance.To a mixture of 445 mg of the resulting compound, 144 mg ofcyclopropylboric acid, 724 mg of potassium phosphate, 65 mg oftricyclohexylphosphine, and 28 mg of palladium(II) acetate were added 10ml of toluene and 0.5 ml of water, followed by stirring at 110° C. for12 hours. The reaction mixture was filtered through celite and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 379 mg of t-butyl5-cyclopropyl-6-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a pale brown foamed substance.

Preparation Example 334

To a solution of 500 mg of t-butyl3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 10 ml of DMF were added 250 μl of 1-(bromomethyl)-3-fluorobenzene and800 mg of cesium carbonate, followed by stirring at 50° C. for 16 hoursunder an argon atmosphere. The reaction mixture was cooled to roomtemperature, and water added, followed by extraction with ethyl acetatetwice. The combined organic layer was washed with saturated brine andthen dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 609 mg of t-butyl4-(3-fluorobenzyl)-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.

Preparation Example 339

To a solution of 600 mg of t-butyl2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 9 ml DMF were added 426 mg of potassium t-butoxide and 451 μl ofbenzyl bromide in an ice-bath, followed by stirring at room temperaturefor 3 hours. Water and ethyl acetate were added thereto, and the organiclayer was concentrated under reduced pressure. The residue was purifiedby silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 644mg of t-butyl1-benzyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a pale yellow solid.

Preparation Example 344

To a solution of 3.83 g of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in40 ml of dichloromethane were added 1.3 ml of pyridine and 1.29 g oftriphosgene under ice-cooling, followed by stirring for 3 hours. Thereaction mixture was concentrated under reduced pressure, diluted withethyl acetate, washed with water and an aqueous ammonium chloridesolution, dried over anhydrous magnesium sulfate, and then filtered, andthe filtrate was concentrated under reduced pressure. To the residue wasadded hexane, followed by stirring, and the solid was collected byfiltration and dried to obtain 3.07 g of t-butyl1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a white solid.

Preparation Example 345

To a solution of 200 mg of t-butyl1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 2 ml of pyridine was added 140 μl of phenethyl alcohol, followed bystirring at 100° C. for 5.5 hours. The reaction mixture was concentratedunder reduced pressure and the residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 68 mg of 8-t-butyl1-(2-phenylethyl)3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-dicarboxylateas a yellow viscous substance.

Preparation Example 349

To a solution of 200 mg of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate and318 mg of 2-(2-methoxyphenyl)ethyl 4-nitrophenylcarbonate in 5 ml ofdichloroethane was added 0.11 ml of pyridine, followed by stirring atroom temperature for 2 days. The reaction mixture was concentrated underreduced pressure and the residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) and basic silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 243 mg of8-t-butyl1-[2-(methoxyphenyl)ethyl]-3,4,6,7,9,10-hexahydro-1H-azepino[4,5-g]quinoline-1,8(2H)-carboxylateas a pale yellow viscous substance.

Preparation Example 367

To a solution of 150 mg of t-butyl11-chloro-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-caxboxylatein 3 ml of tetrahydrofuran was added 1.5 ml of a 1 M aqueous sodiumhydrogen carbonate solution, followed by ice-cooling, and 64 μl of ethylchloroformate was added dropwise thereto followed by stirring. Thereaction mixture was diluted with ethyl acetate, washed with water andsaturated brine, dried over anhydrous magnesium sulfate, and thenfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 149 mg of 8-t-butyl4-ethyl-1′-chloro-2,3,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-4,8-dicarboxylateas a colorless foamed substance.

Preparation Example 375

To 500 mg of t-butyl11-bromo-1-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate,350 mg of potassium carbonate, 290 mg of copper iodide, 173 mg of1H-pyrazole, and 313 mg of N,N-dimethylglycine was added 6.25 ml ofdimethylsulfoxide under argon, followed by stirring at 135° C. for 36hours. To the reaction mixture were added water and ethyl acetate,followed by stirring, and then the solid was separated by filtration.The organic layer was washed with aqueous sodium bicarbonate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (elution solvent: HEX-EtOAc) to obtain 43 mg oft-butyl1-methyl-1′-(1H-pyrazol-1-yl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless viscous liquid.

Preparation Example 376

A solution of 200 mg of t-butyl11-bromo-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate,34 mg of zinc cyanide, 13 mg of bis(tri-t-butylphosphine)palladium, and10 mg of zinc powder in 4 ml of N,N-dimethylacetamide was substitutedwith argon and then stirred at 100° C. for 15 hours. The reactionmixture was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 132 mg of t-butyl11-cyano-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless viscous substance.

Preparation Example 377

1.1946 g of1-[11-bromo-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-yl]-2,2,2-trifluoroethanone,2.2395 g of sodium trifluoroacetate, and 1.568 g of copper iodide wereadded to 24 ml of N-methylpyrrolidone under an argon atmosphere,followed by stirring at 170° C. for 18 hours. To the reaction mixturewere added water and ethyl acetate, and filtered through celite wasperformed. The filtrate was subjected to liquid separation, the organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and then filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography(elution solvent: Hex-AcOEt) to obtain 239 mg of2,2,2-trifluoro-1-[1-(2-methoxyethyl)-11-(trifluoromethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-yl]ethanoneas a pale yellow solid.

Preparation Example 379

To 7.87 g of 3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoicacid were added 200 ml of t-butanol, 7 ml of triethylamine, and 5 ml ofdiphenylphosphoryl azide, followed by heating and refluxing for 70hours. The reaction mixture was cooled to room temperature, then dilutedby the addition of water, and stirred, and the solid was collected byfiltration and dried to obtain 9.49 g oft-butyl[2-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamateas a pale brown solid. Further, the solid precipitated from the filtratewas collected by filtration to obtain 665 mg oft-butyl[2-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamateas a white solid.

Preparation Example 380

670 mg of t-butyl1-[(benzyloxy)methyl]-6-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatewas stirred at room temperature for 3.5 hours in a 48% aqueoushydrobromic acid solution. The reaction mixture was extracted withhexane and a side-product, benzyl bromide, was removed. Then, theaqueous layer was alkalified by the addition of a 1 M aqueous sodiumhydroxide solution, and 20 ml of tetrahydrofuran was added thereto. Tothe mixed liquid was added 500 mg of di-t-butyl dicarbonate, followed bystirring at room temperature for 2 hours. The reaction mixture wasextracted with ethyl acetate and the organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and thenfiltered. The filtrate was concentrated under reduced pressure to obtain513 mg of t-butyl6-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a colorless foamed substance.

Preparation Example 381

Under an argon atmosphere, to a solution of 1.7 g of ethyl7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in30 ml of DMF was added 283 mg of sodium hydride under ice-cooling,followed by stirring at the same temperature for 10 minutes. Then, 1.54g of t-butyl(4R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylate was addedthereto, followed by stirring at room temperature for 18 hours. To thereaction mixture was added water and 1 M aqueous hydrochloric acidsequentially, followed by stirring, and the precipitated solid wascollected by filtration. To 20 ml of a suspension of the resulting solidin ethanol was added 10 ml of a 4 M hydrogen chloride-ethyl acetatesolution under ice-cooling, followed by stirring at 60° C. for 1 hour.The reaction mixture was evaporated under reduced pressure, and to theresidue were added chloroform and saturated aqueous sodium bicarbonate.After extraction with chloroform, the combined organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure to obtain 2.26 g of ethyl7-{[(2R)-2-aminopropyl]oxy}-8-bromo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateas an opaque cream-colored oily substance.

Preparation Example 383

Under an argon atmosphere, to a solution of 1.64 g of ethyl7-{[(2R)-2-aminopropyl]oxy}-8-bromo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 41 ml of toluene were added 509 mg of sodium t-butoxide, 275 mg of2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 202 mg oftris(dibenzylideneacetone)dipalladium (0) in this order, followed byheating at 100° C. for 24 hours. Further, 509 mg of sodium t-butoxide,275 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 202 mg oftris(dibenzylideneacetone)dipalladium (0) were added thereto, followedby stirring at 100° C. for additional 24 hours. The reaction mixture wasreturned to room temperature, then filtered through celite, and washedwith ethyl acetate, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutionsolvent: Hex-AcOEt) to obtain 610 mg of ethyl(3R)-3-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.

Preparation Example 385

Under an argon atmosphere, to a solution of 1.032 g of ethyl7-[(3-methylbut-2-enoyl)amino]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylatein 10.5 ml of dichloromethane was added 870 mg of aluminum chloride atroom temperature, followed by stirring at room temperature for 3 hours.Further, 435 mg of aluminum chloride was added thereto, followed bystirring at room temperature for 2 hours. The reaction mixture waspoured into ice-water, followed by extraction with chloroform. Thecombined organic layer was washed with water, a saturated aqueous sodiumhydrogen carbonate solution, water, and saturated brine, dried overanhydrous magnesium sulfate, and then filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (elution solvent: Hex-AcOEt) to obtain 431 mg ofethyl4,4-dimethyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylateas a white solid.

Preparation Example 386

Under an argon atmosphere, to a solution of 1 g of ethyl7-amino-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and 539 mg of1,1-dimethylprop-2-in-1-yl acetate in 10 ml of tetrahydrofuran was added43 mg of copper chloride, followed by heating at 90° C. for 5 hours. Thereaction mixture was concentrated under reduced pressure, ethyl acetateadded, and washed with a saturated aqueous ammonium chloride solution,and saturated brine. The aqueous layer was extracted with ethyl acetatetwice, the combined organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and then filtered, and the filtratewas concentrated under reduced pressure. The residue was purified bypreparative thin layer chromatography to obtain 272 mg of ethyl2,2-dimethyl-1,2,6,7,9,10-hexahydro-8H-azepine[4,5-g]quinoline-8-carboxylate.

Preparation Example 387

To ethyl 7-amino-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate wasadded a 5% aqueous sulfuric acid solution, followed by stirring underice-cooling. An aqueous solution (30 ml) of 10.22 g of sodium nitritewas added dropwise in portions thereto, and followed by stirring at thesame temperature for 0.5 hours and then stirring at 60° C. for 3 hours.The reaction mixture was extracted with ethyl acetate, the organic layerwas dried over anhydrous magnesium sulfate and then filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain a crude purified product having ethyl7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a maincomponent. The crude purified product was recrystallized from ethylacetate twice to obtain 15.66 g of ethyl7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate.

Preparation Example 388

To a solution of 30 g of ethyl7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 300 ml ofethanol was added 3 g of 10% palladium on carbon, followed by stirringat room temperature for 16 hours under a hydrogen atmosphere of 4 atm.The reaction mixture was filtered through celite, and the filtrate wasice-cooled and then 21.6 ml of anhydrous acetic acid was added dropwisethereto, followed by stirring for 16 hours. The reaction mixture wasconcentrated under reduced pressure and to the residue was addeddiethylether to wash the solid, thereby obtaining 26.45 g of ethyl7-acetamide-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a whitesolid.

Preparation Example 389

The mixed liquid of 12 g of ethyl7-acetamide-8-bromo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate,1.93 g of copper iodide, 1.89 g of 1,10-phenanthroline, and 33.12 g ofcesium carbonate in 240 ml of dioxane was substituted with argon,followed by stirring at 100° C. for 18 hours. The reaction mixture wasdiluted with ethyl acetate, the insoluble materials were removed usingcelite, and the filtrate was concentrated under reduced pressure toobtain a milky white solid. The resulting residue was suspended in 240ml of dioxane, and 1.93 g of copper iodide, 1.89 g of1,10-phenanthroline, and 33.1 g of cesium carbonate were added thereto,followed by stirring at 100° C. for 3 days. The reaction mixture wascooled to room temperature, diluted with ethyl acetate, and filteredthrough celite to remove the solid, and the filtrate was concentratedunder reduced pressure to obtain 9.245 g of ethyl2-methyl-5,6,8,9-tetrahydro-7H-[1,3]oxazolo[4,5-h][3]benzazepine-7-carboxylateas a milky white solid.

Preparation Example 390

To a solution of 7 g of ethyl2-methyl-5,6,8,9-tetrahydro-7H-[1,3]oxazolo[4,5-h][3]benzazepine-7-carboxylatein 130 ml of ethanol was added 130 ml of 1 M aqueous hydrochloric acid,followed by stirring for 16 hours. Ethanol was evaporated under reducedpressure, dried, dissolved in chloroform, and washed with water. Theorganic layer was dried over anhydrous sodium sulfate and then thesolvent was evaporated under reduced pressure to obtain 6.84 g of ethyl7-acetamide-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateas a brownish white solid.

Preparation Example 408

To a solution of 860 mg of t-butyl4-ethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 25 ml of dichloroethane was added 1.1 g of sodium hydrogen carbonate,and further, a solution of 200 μl of bromine in 5 ml of dichloroethanewas added dropwise thereto over about 30 minutes, followed by stirringat room temperature. To the reaction mixture was slowly added a 3%aqueous sodium thiosulfate solution, followed by stirring vigorously andextracting with chloroform twice. The combined organic layer was washedwith saturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated and the residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 490 mg of t-butyl5-bromo-4-ethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.

Preparation Example 409

Under an argon atmosphere, to a mixed solution of 5.0 g of ethyl7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 100 ml ofdichloromethane and 20 ml of methanol was added portionwise 8.05 g ofN,N,N-trimethylanilinium tribromide under ice-cooling, followed bystirring at the same temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, the residue was extracted by theaddition of ethyl acetate and water, and the organic layer was washedwith 1 M aqueous hydrochloric acid and saturated brine, dried overanhydrous magnesium sulfate, and then filtered, and the filtrate wasconcentrated under reduced pressure to obtain 6.67 g of ethyl7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as abeige solid.

Preparation Example 411

To a solution of 150 mg of t-butyl1-(3-methoxypropyl)-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 4.2 ml of acetonitrile were added 107 mg of N-bromosuccinimide and3.7 mg of ammonium nitrate, followed by stirring at room temperature for3.5 hours. The reaction mixture was concentrated to about ¼, and ethylacetate, an aqueous sodium thiosulfate solution, and aqueous sodiumbicarbonate was added thereto. The organic layer was washed withsaturated brine and then dried over anhydrous magnesium sulfate. Thesolvent was evaporated to obtain 198 mg of t-butyl11-bromo-1-(3-methoxypropyl)-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.

Preparation Example 426

To a solution of 16.23 g of ethyl3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoate in 200 ml ofethanol was added 150 ml of a 1 M aqueous sodium hydroxide solution,followed by stirring at room temperature for 2 hours. The reactionmixture was made weakly acidic by the addition dropwise of concentratedhydrochloric acid and diluted by the addition of water. The precipitatedsolid was collected by filtration and dried to obtain 8.88 g of3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoic acid as a palebrown solid.

Preparation Example 427

To 3.421 g of ethyl8-acetamide-6-bromo-7-(2-ethoxy-2-oxoethoxy)-1,2,4,5-tetrahydro-3H-benzazepine-3-carboxylatewere added 30 ml of acetic acid and 30 ml of 8 M hydrochloric acid,followed by stirring at 150° C. for 16 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved in 35ml of THF, and alkalified by the addition of 35 ml of a 1 M aqueoussodium hydroxide solution. 2 g of di-t-butyl dicarbonate was addedthereto, followed by stirring at room temperature for 1 hour. Thereaction mixture was extracted with ethyl acetate, the organic layer wasdried over anhydrous magnesium sulfate and then filtered, and thefiltrate was concentrated under reduced pressure to obtain 1.373 g oft-butyl11-bromo-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.

Preparation Example 495

To a solution of 590 mg of t-butyl4-benzyl-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 10 ml of tetrahydrofuran was added 3.5 ml of a 1 M solution of aborane-THF complex in THF under ice-cooling, followed by stirring atroom temperature for 14 hours. The reaction mixture was cooled, and MeOHand a 1 M aqueous sodium hydroxide solution were added thereto, followedby stirring at room temperature for 3 hours. The reaction mixture wasconcentrated, to the residue were added ethyl acetate and water, and theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated, and to a solution of 578 mgof the resulting residue in 10 ml of dichloromethane was added 620 mg ofsodium hydrogen carbonate. Further, a solution of 280 mg of bromine in 5ml of dichloromethane was added dropwise thereto over about 30 minutes,followed by stirring at room temperature. To the reaction mixture wasslowly added a 3% aqueous sodium thiosulfate solution, followed bystirring vigorously and extracting with chloroform twice. The combinedorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and then filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (elution solvent: HEX-EtOAc) to obtain 518 mg of t-butyl4-benzyl-5-bromo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.

Preparation Example 540

To a solution of 210 mg of 2,4,5-trifluorobenzonitrile and 500 mg oft-butyl5-cyclopropyl-4-(2-hydroxyethyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 15 ml of THF was added portionwise 150 mg of potassium t-butoxide,followed by stirring at −30° C. for 2 hours. Further, to the reactionmixture was added 0.15 ml of MeOH and then 150 mg of potassiumt-butoxide was added portionwise thereto, followed by elevating thetemperature to −10° C. and stirring for 15 hours. Further, to thereaction mixture were added 0.15 ml of MeOH, and then 150 mg ofpotassium t-butoxide was added portionwise thereto, followed byelevating the temperature to 0° C. and stirring for additional 14 hours.The reaction mixture was diluted with ethyl acetate, washed with waterand saturated brine, dried over anhydrous magnesium sulfate, and thenfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (elution solvent:HEX-EtOAc)) to obtain 726 mg of t-butyl4-[2-(4-cyano-2-fluoro-5-methoxyphenoxy)ethyl]-5-cyclopropyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a colorless viscous substance.

Preparation Example 543

To a solution of 270 mg of t-butyl5-cyclopropyl-4-[2-(2,6-difluoro-4-formylphenoxy)ethyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 6 ml of MeOH was added 30 mg of sodium borohydride, followed bystirring at room temperature for 4 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (elution solvent: HEX-EtOAc)) to obtain 220 mgof t-butyl5-cyclopropyl-4-{2-[2,6-difluoro-4-(hydroxymethyl)phenoxy]ethyl}-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a white solid.

Preparation Example 545

To a solution of 400 mg of t-butyl5-cyclopropyl-4-(2-hydroxyethyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 4 ml of dichloromethane were added 217 mg of p-toluenesulfonylchloride, 0.22 ml of triethylamine, and 125 μl of N-methylimidazole inthis order, followed by stirring for 1 hour. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (elution solvent: HEX-EtOAc) to obtain 541 mgof t-butyl5-cyclopropyl-4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(211)-carboxylateas a white solid.

Preparation Example 549

To 400 mg of t-butyl5-cyclopropyl-4-[(2R)-2-methoxy-3-{[(4-methylphenyl)sulfonyl]oxy}propyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatewas added 7 ml of a 1 M solution of tetrabutylammonium fluoride in THF,followed by heating and stirring at 60° C. for 13 hours under an argonatmosphere. The reaction mixture was cooled to room temperature and asaturated aqueous sodium hydrogen carbonate solution was added thereto,followed by extraction with ethyl acetate twice. The combined organiclayer was dried over anhydrous sodium sulfate and then filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (elution solvent: HEX-EtOAc) toobtain 257 mg of t-butyl5-cyclopropyl-4-[(2R)-3-fluoro-2-methoxypropyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a white foamed solid.

Preparation Example 565

To a solution of 300 mg of t-butyl5-cyclopropyl-4-(2-hydroxy-3-methoxypropyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 3 ml of toluene were added 0.1 ml of o-fluorophenol and 250 mg ofcyanomethylenetributylphosphorane, followed by stirring at 80° C. for 20hours. The reaction mixture was concentrated under reduced pressure andthe residue was purified by silica gel chromatography (elution solvent:HEX-EtOAc) to obtain 277 mg of t-butyl5-cyclopropyl-4-[2-(2-fluorophenoxy)-3-methoxypropyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateas a pale yellow viscous substance.

In the same manner as in the methods of Preparation Examples above, thecompounds of Preparation Examples as shown in the Tables below wereprepared. For the compounds of the Preparation Examples, the structuresare shown in Tables 2 to 81 and the preparation methods and thephysicochemical data are shown in Tables 82 to 96.

Example 1

To 1.865 g of ethyl11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatewere added 20 mL of ethylene glycol and 20 mL of a 40% aqueous potassiumhydroxide solution, followed by heating to 120° C. for 18 hours. Thereaction mixture was ice-cooled and adjusted to pH 1 by the addition ofconcentrated hydrochloric acid, followed by stirring for 1 hour. Thereaction mixture was alkalified by the addition of a 1 M aqueous sodiumhydroxide solution, followed by extraction with chloroform. The organiclayer was dried over anhydrous sodium sulfate and then filtered. Thefiltrate was concentrated under reduced pressure to obtain 1.451 g of11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one asa brown solid. To 60 mg of11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-onewere added 1 ml of EtOAc and then EtOH, followed by dissolution underheating. The precipitated solid was collected by filtration to obtain29.5 mg of11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one asa white solid.

Example 2

To 47 mg of t-butyl11-chloro-1-isobutyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatewas added 1 ml of a 4 M hydrogen chloride solution in EtOAc, followed bystirring at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was purified byamino-silica gel chromatography (elution solvent: chloroform-MeOH). 26mg of the resulting pale yellow viscous substance was dissolved in EtOH,followed by addition of 10.3 mg of fumaric acid and stirring. Theprecipitated solid was collected by filtration to obtain 23.2 mg of11-chloro-1-isobutyl-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinolinemonofumarate as a white solid.

Example 3

To a solution of 200 mg of t-butyl2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 2 ml of THF was added 1.9 ml of a 1 M solution of a borane-THFcomplex in THF under ice-cooling, followed by elevating the temperatureto room temperature and stirring for 6 hours, and then elevating thetemperature to 45° C. After stirring for 3 hours, 1.9 ml of a 1 Msolution of a borane-THF complex in THF was added thereto in anice-bath. After an additional 2 hours, MeOH was added dropwise thereto,followed by stirring for 20 minutes. The mixed solution was diluted withwater, followed by extraction with chloroform. The organic layer wasdried over anhydrous sodium sulfate and then filtered, and the filtratewas concentrated under reduced pressure. The residue was dissolved in1.6 ml of dichloromethane, and 0.4 ml of trifluoroacetic acid was addedthereto, followed by stirring at room temperature for 1 hour and thenconcentrating under reduced pressure. The residue was purified by silicagel chromatography (elution solvent: chloroform-MeOH— aqueous ammonia),and the resulting solid was dissolved in 0.25 ml of hot EtOH, followedby addition of 21 mg of fumaric acid. While stirring, the resultant wascooled to room temperature and the precipitated solid was filtered toobtain 36 mg of 2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinolinemonofumarate as a pale yellow solid.

Example 4

To 150 mg of ethyl1-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatewere added 4 ml of ethylene glycol and 2 ml of a 40% aqueous potassiumhydroxide solution, followed by heating at 120° C. and stirring for 18hours. The reaction mixture was ice-cooled and the liquid was madeacidic by the addition of concentrated hydrochloric acid, followed bystirring for an additional 1 hour. The reaction mixture was neutralizedwith a 1 M aqueous sodium hydroxide solution and then extracted withchloroform, the organic layer was dried over anhydrous sodium sulfateand then filtered, and the filtrate was concentrated under reducedpressure. Then, the residue was purified by silica gel chromatography(elution solvent: chloroform-MeOH-aqueous ammonia). To a solution of theresulting residue in 2 ml of EtOAc was added 0.2 ml of a 4 M hydrogenchloride solution in EtOAc, followed by stirring. The solvent wasconcentrated under reduced pressure and the resulting solid wasdissolved in 2 ml of EtOH under heating, followed by stirring at roomtemperature. The precipitated solid was collected by filtration toobtain 43.7 mg of1-methyl-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-onemonohydrochloride as a pale yellow solid.

Example 5

To a solution of 140 mg of t-butyl11-cyclopropyl-1-(methoxyacetyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 1 ml of EtOH was added 2 ml of 4 M hydrogen chloride solution inEtOAc, followed by stirring at room temperature for 3 hours. Thereaction mixture was poured into a 1 M aqueous sodium hydroxidesolution, the aqueous layer was extracted with chloroform, and theorganic layer was dried over sodium sulfate. The solvent wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel chromatography (elution solvent:chloroform-MeOH-aqueous ammonia) to obtain 102 mg of11-cyclopropyl-1-(methoxyacetyl)-2,3,4,6,7,8,9,10-octahydro-8H-azepino[4,5-g]quinolineas a pale yellow oily substance.

Example 6

To a solution of 200 mg of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in2.13 ml of dichloroethane were added 0.553 ml of triethylamine and 0.19ml of ethyl chloroformate, followed by stirring at 60° C. for 2 hours.The reaction mixture was cooled to room temperature, and then thereaction mixture was diluted with EtOAc, washed with 1 M hydrochloricacid, water, a 1 M aqueous sodium hydroxide solution, and saturatedbrine, and concentrated, and the residue was purified by silica gelcolumn chromatography (elution solvent: HEX-EtOAc). The resultingsubstance was dissolved in chloroform, followed by adding 0.05 ml oftrifluoroacetic acid and stirring for 30 minutes. After concentrationunder reduced pressure, the resultant was dissolved in EtOH, neutralizedby the addition of triethylamine, and then concentrated under reducedpressure. Then, the residue was purified by silica gel columnchromatography (elution solvent: chloroform-MeOH-aqueous ammonia). Theresulting substance was dissolved in EtOH and 76 mg of fumaric acid wasadded thereto. The resulting white solid was collected by filtration anddried to obtain 79 mg of ethyl2,3,4,6,7,8,9,10-octahydro-1H-azepino[4.5-g]quinoline-1-carboxylatehemifumarate.

Example 7

To a solution of 300 mg of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in5.26 ml of pyridine was added 0.455 ml of N,N-dimethylcarbamoylchloride, followed by stirring at 80° C. for 3 hours. To the reactionmixture was added 1 M hydrochloric acid, followed by extraction withEtOAc. The organic layer was washed with saturated brine and the solventwas evaporated. The resulting residue was purified by silica gel columnchromatography (elution solvent: HEX-EtOAc). The resulting substance wasdissolved in 6 ml of chloroform, followed by adding 3 ml oftrifluoroacetic acid and stirring for 30 minutes. After concentrationunder reduced pressure, the resultant was dissolved in 4.5 ml of EtOH,neutralized by the addition of triethylamine, and then concentratedunder reduced pressure. Then, the residue was purified by silica gelcolumn chromatography (elution solvent: chloroform-MeOH-aqueousammonia). The resulting substance was dissolved in 4.5 ml of EtOH and115 mg of fumaric acid was added thereto. The resulting white solid wascollected by filtration and dried to obtain 120 mg ofN,N-dimethyl-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline-1-carboxamidefumarate.

Example 8

To a solution of 300 mg of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 6ml of toluene was added 1.16 ml of ethyl isocyanate, followed bystirring at 90° C. overnight. The reaction mixture was concentratedunder reduced pressure and then purified by silica gel columnchromatography (elution solvent: HEX-EtOAc). The resulting substance wasdissolved in 7.5 ml of chloroform, followed by adding 3 ml oftrifluoroacetic acid and stirring for 30 minutes. After concentrationunder reduced pressure, the resultant was dissolved in 4.5 ml of EtOH,neutralized by the addition of triethylamine, and then concentratedunder reduced pressure. Then, the residue was purified by silica gelcolumn chromatography (elution solvent: chloroform-MeOH-aqueousammonia). The resulting substance was dissolved in EtOH and 115 mg offumaric acid was added thereto. The resulting white solid was collectedby filtration and dried to obtain 247 mg ofN-ethyl-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline-1-carboxamidemonofumarate.

Example 9

To a solution of 200 mg of t-butyl1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 6ml of dichloromethane were added 0.148 ml of triethylamine, 0.093 ml ofethanesulfonyl chloride, and 54 mg of 1-methylimidazole underice-cooling, followed by stirring at room temperature overnight. To thereaction mixture were added EtOAc and saturated brine, and the organiclayer was washed with saturated brine and then concentrated underreduced pressure. The residue was purified by silica gel chromatography(elution solvent: HEX-EtOAc). The resulting substance was dissolved in 4ml of chloroform, followed by adding 2 ml of trifluoroacetic acid andstirring for 30 minutes. After concentration under reduced pressure, theresultant was dissolved in 4.5 ml of EtOH, neutralized by the additionof triethylamine, and then concentrated under reduced pressure. Then,the residue was purified by silica gel column chromatography (elutionsolvent: chloroform-MeOH-aqueous ammonia). The resulting substance wasdissolved in EtOH and 76 mg of fumaric acid was added thereto. Theresulting white solid was collected by filtration and dried to obtain 61mg of1-(ethylsulfonyl)-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinolinemonofumarate.

Example 112

To a solution of 283 mg of t-butyl4-(3-chlorobenzyl)-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylatein 1.8 ml of tetrahydrofuran was added 1.46 ml of a 1 M solution of aborane-THF complex in THF, followed by stirring at 50° C. for 4 hours.The reaction mixture was ice-cooled, and MeOH was added thereto,followed by stirring at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure and MeOH was addedthereto, followed by concentration again. The residue was dissolved in2.8 ml of EtOH, and 4 M hydrogen chloride-ethyl acetate solution wasadded thereto, followed by stirring overnight. After concentration underreduced pressure, the resultant was dissolved in EtOH, neutralized bythe addition of triethylamine, and concentrated under reduced pressure.Then, the residue was purified by silica gel column chromatography(elution solvent: chloroform-MeOH). The resulting substance wasdissolved in ethanol and fumaric acid was added thereto, followed bystirring for a while. The solid was generated, then dissolved by heatingonce, and stirred at room temperature for 3 hours. The resulting whitesolid was collected by filtration and dried to obtain 23 mg of4-(3-chlorobenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepinefumarate.

Example 282

To a solution of 606 mg of t-butyl11-bromo-1-(2-methoxyethyl)-10-methyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylatein 6 ml of dichloromethane was added 3 ml of trifluoroacetic acid,followed by stirring at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure and the residue waspurified by basic silica gel chromatography (elution solvent:chloroform-MeOH). 150 mg of the resulting residue was collected byseparation using DAICEL CHIRALPAK AD-H (2 cmφ×25 cm) to obtain 51 mg ofa low-polarity material and 45 mg of a high-polarity material. Each wasdissolved in ethanol and fumaric acid was added thereto to form a salt.The precipitated solid was recrystallized from ethanol to obtain 42 mgand 36 mg of enantiomers of11-bromo-1-(2-methoxyethyl)-10-methyl-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinolinefumarate as white solids, respectively.

In this regard, while the products are shown with a single planarstructure in the Tables below with respect to the compounds of Example282, and Example 280 and Example 281 in which preparation was performedas in Example 282, each of two kinds of enantiomers was isolated andobtained similarly as described above but the stereochemistryidentification was not carried out.

In the same manner as in the methods of Examples above, the compounds ofExamples shown in the Tables below were prepared. The structure of thecompounds of the Examples are shown in Tables 97 to 147 and thepreparation methods and the physicochemical data are shown in Tables 148to 181.

Furthermore, the structures of the other compounds of the presentinvention are shown in Tables 182 to 190. These can be easilysynthesized by the methods described in the preparation methods andExamples above, methods apparent to a person skilled in the art, ormodified methods thereof.

TABLE 2 PEx Str 1

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TABLE 3 PEx Str  9

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TABLE 4 PEx Str 18

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TABLE 5 PEx Str 26

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TABLE 6 PEx Str 34

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TABLE 7 PEx Str 42

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TABLE 8 PEx Str 52

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TABLE 9 PEx Str 61

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TABLE 10 PEx Str 70

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TABLE 11 PEx Str 79

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TABLE 12 PEx Str 87

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TABLE 13 PEx Str 95

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TABLE 14 PEx Str 103

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TABLE 15 PEx Str 110

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TABLE 16 PEx Str 116

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TABLE 17 PEx Str 122

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TABLE 18 PEx Str 130

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TABLE 19 PEx Str 137

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TABLE 20 PEx Str 144

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TABLE 21 PEx Str 152

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TABLE 22 PEx Str 159

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TABLE 23 PEx Str 166

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TABLE 24 PEx Str 175

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TABLE 25 PEx Str 182

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TABLE 26 PEx Str 190

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TABLE 27 PEx Str 198

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TABLE 28 PEx Str 205

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TABLE 29 PEx Str 212

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TABLE 30 PEx Str 218

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TABLE 31 PEx Str 224

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TABLE 32 PEx Str 231

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TABLE 33 PEx Str 238

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TABLE 34 PEx Str 245

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TABLE 35 PEx Str 251

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TABLE 36 PEx Str 258

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TABLE 37 PEx Str 265

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TABLE 38 PEx Str 272

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TABLE 39 PEx Str 278

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TABLE 40 PEx Str 284

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TABLE 41 PEx Str 290

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TABLE 42 PEx Str 298

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TABLE 43 PEx Str 304

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TABLE 44 PEx Str 311

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TABLE 45 PEx Str 317

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TABLE 46 PEx Str 324

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TABLE 47 PEx Str 331

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TABLE 48 PEx Str 338

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TABLE 49 PEx Str 346

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TABLE 50 PEx Str 354

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TABLE 51 PEx Str 362

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TABLE 52 PEx Str 370

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TABLE 53 PEx Str 378

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TABLE 54 PEx Str 387

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TABLE 55 PEx Str 394

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TABLE 56 PEx Str 402

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TABLE 57 PEx Str 409

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TABLE 58 PEx Str 417

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TABLE 59 PEx Str 424

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TABLE 60 PEx Str 432

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TABLE 61 PEx Str 440

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TABLE 62 PEx Str 447

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TABLE 63 PEx Str 454

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TABLE 64 PEx Str 460

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TABLE 65 PEx Str 468

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TABLE 66 PEx Str 475

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TABLE 67 PEx Str 482

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TABLE 68 PEx Str 488

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TABLE 69 PEx Str 494

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TABLE 70 PEx Str 500

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TABLE 71 PEx Str 506

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TABLE 72 PEx Str 514

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TABLE 73 PEx Str 522

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TABLE 74 PEx Str 528

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TABLE 75 PEx Str 534

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TABLE 76 PEx Str 540

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TABLE 77 PEx Str 545

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TABLE 78 PEx Str 551

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TABLE 79 PEx Str 557

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TABLE 80 PEx Str 563

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TABLE 81 PEx Str 569

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TABLE 82 PEx Psyn Dat 1 1 EI: 296, 298, 300 2 2 EI: 190, 192 3 3 EI:209, 211 4 4 ESI+: 254, 256 5 5 FAB+: 299, 301 6 6 EI: 268, 270 7 7 EI:346, 348, 350 8 8 ESI+: 367, 369 9 9 EI: 322, 324 10 10 ESI+: 351, 35311 11 ESI+: 337, 339 12 12 ESI+: 351, 353 13 13 ESI+: 407 14 14 APCI+:220 15 15 ESI+; 303 16 71 ESI+; 331 17 17 ESI+; 359 18 18 ESI+; 317 1919 ESI+; 345 20 20 ESI+; 419 21 21 ESI+: 403 22 22 ESI+: 417([M + Na]⁺)23 23 FAB−: 331 24 24 ESI+: 333 25 25 ESI+: 361 26 26 ESI+: 383,405([M + Na]⁺) 27 27 ESI+: 448 28 28 ESI+: 350 29 29 ESI+: 393 30 30ESI+: 349 31 31 ESI+: 331 32 32 ESI+: 388 33 33 ESI+: 389 34 34 ESI+:291 35 35 ESI+: 403 36 36 FAB+: 537 37 37 ESI+: 577 38 38 ESI+: 473([M +Na]⁺) 39 39 EI: 315 40 40 FAB+: 320

TABLE 83 PEx Psyn Dat 41 41 FAB+: 333 42 42 ESI+: 359 43 27 EI: 181 44 4ESI+: 182, 184 45 19 ESI+: 235 46 7 EI; 312 47 8 ESI+; 333 48 5 EI; 26449 9 EI; 288 50 22 ESI+: 403([M + Na]⁺) 51 15 ESI+: 333 52 11 ESI+: 31953 11 ESI+: 365, 367 54 11 ESI+: 305 55 13 ESI+: 393, 395 56 13 ESI+:407, 409 57 13 ESI+: 409, 411 58 23 FAB−: 317 59 11 ESI+; 317 60 15ESI+: 347, 369([M + Na]⁺) 61 11 ESI+: 379, 381 62 11 ESI+: 395, 397 6311 ESI+: 393, 395 64 11 ESI+: 333 65 11 ESI+: 319 66 25 ESI+: 333 67 7ESI+: 383, 385 68 18 ESI+: 319 69 25 ESI+: 347 70 24 APCI+: 333 71 71ESI+; 317 72 11 ESI+; 303 73 7 ESI+: 381, 383 74 11 ESI+; 331 75 13FAB+; 345 76 24 ESI+: 397, 399 77 13 ESI+; 373 78 18 ESI+: 345 79 13ESI+: 405, 407 80 13 ESI+: 419, 421

TABLE 84 PEx Psyn Dat 81 11 ESI+: 391, 393 82 11 ESI+: 405, 407 83 13ESI+: 433, 435 84 13 ESI+: 441, 443 85 18 ESI+; 379 86 15 ESI+; 331 8711 ESI+: 419, 421 88 11 ESI+: 427, 429 89 13 ESI+: 447, 449 90 11 ESI+:433, 435 91 22 ESI+: 431([M + Na]⁺) 92 23 FAB−: 331 93 11 ESI+: 319 9424 ESI+: 363 95 24 ESI+: 359 96 13 ESI+: 375 97 24 ESI+: 361 98 15 ESI+:391 99 11 ESI+: 377 100 15 ESI+: 431([M + Na]⁺) 101 15 ESI+: 375 102 17ESI+: 437 103 11 ESI+: 395 104 11 ESI+: 361 105 15 ESI+: 391 106 11ESI+: 377 107 15 ESI+: 417 108 11 ESI+: 403 109 7 ESI+: 361 110 18 ESI+:381 111 17 ESI+; 361 112 18 ESI+; 409 113 18 ESI+; 447, 449 114 18 ESI+;413, 415 115 17 ESI+; 471, 473 116 17 ESI+; 505, 507 117 18 ESI+; 397118 17 ESI+; 465 119 12 ESI+: 363 120 13 ESI+: 403

TABLE 85 PEx Psyn Dat 121 17 ESI+; 467 122 17 ESI+; 455 123 15 ESI+; 375124 18 ESI+; 343 125 17 ESI+; 399 126 17 ESI+; 401 127 15 ESI+: 405 12811 ESI+: 391 129 11 ESI+: 389 130 18 ESI+: 395 131 13 ESI+: 467 132 11ESI+: 453 133 15 ESI+: 391 134 15 ESI+: 405 135 11 ESI+: 377 136 11ESI+: 391 137 18 ESI+; 343 138 13 ESI+: 439([M + Na]⁺) 139 12 ESI+: 347140 11 ESI+: 403 143 11 ESI+: 389 144 22 ESI+: 406 145 27 ESI+: 226 14627 EI: 195 149 21 ESI+: 387 150 17 ESI+; 403 151 28 ESI+: 392 152 13ESI+: 391 153 29 ESI+: 322 154 41 ESI+: 421 155 41 ESI+: 393 156 11ESI+: 319 157 42 ESI+: 397, 399 158 11 ESI+: 373 159 18 ESI+: 395,417([M + Na]⁺) 160 13 ESI+: 431

TABLE 86 PEx Psyn Dat 161 13 ESI+: 389 162 13 ESI+: 417 163 11 ESI+: 417164 11 ESI+: 377 165 11 ESI+: 381 166 12 ESI+: 351 167 18 ESI+: 331 16818 ESI+: 345 169 19 ESI+: 333 170 11 ESI+: 375 171 11 ESI+: 361 172 18ESI+: 329 173 19 ESI+; 331 175 13 ESI+: 405 176 21 ESI+: 391 177 17ESI+; 389 178 18 ESI+; 359 179 11 ESI+: 391 180 11 ESI+: 377 181 19ESI+: 347 182 13 FAB+: 419 183 11 ESI+: 277 184 11 ESI+: 405 185 15FAB+: 379 186 11 ESI+: 365 187 13 ESI+: 453([M + Na]⁺) 188 11 ESI+: 417189 13 ESI+: 457, 479([M + Na]⁺) 190 11 ESI+: 443 192 13 ESI+: 431,453([M + Na]⁺) 193 11 ESI+: 417 195 22 NMR: 1.19(3H, t, J = 7.1 Hz),1.38(9H, s), 1.54(6H, s), 2.80-2.93(4H, br), 3.39-3.51(4H, br), 4.20(2H,q, J = 7.1 Hz), 6.79(1H, s), 7.68(1H, s) 196 22 ESI+: 457, 459 197 22ESI+: 413, 415 198 22 ESI+: 431([M + Na]⁺) 199 22 ESI+: 447([M + Na]⁺)200 22 ESI+: 459([M + Na]⁺)

TABLE 87 PEx Psyn Dat 201 18 ESI+: 439 202 18 ESI+: 435 203 18 ESI+: 399204 18 ESI+: 405 205 18 ESI+: 345 206 18 ESI+: 417 207 18 ESI+: 359 20818 ESI+: 457 209 18 ESI+: 417 210 18 ESI+: 465 211 18 ESI+: 403 212 18ESI+: 439 213 18 ESI+: 445 214 18 ESI+: 445 215 18 ESI+: 427 216 18ESI+: 493 217 18 ESI+: 453 218 18 ESI+: 383 219 18 ESI+: 493 220 18ESI+: 529 221 18 ESI+: 535 222 18 ESI+: 385 223 18 ESI+: 427 224 18ESI+: 417 225 18 ESI+: 403 226 18 ESI+: 429, 451([M + Na]⁺) 227 18 ESI+:417 228 18 ESI+: 405, 427([M + Na]⁺) 229 18 ESI+: 401 230 18 ESI+: 395231 18 ESI+: 345 232 18 ESI+: 359 233 18 ESI+: 383 234 18 ESI+: 415 23518 ESI+: 415 236 18 ESI+: 429 237 18 ESI+: 405 238 18 ESI+: 431 239 18ESI+: 347 240 18 ESI+: 391

TABLE 88 PEx Psyn Dat 241 18 ESI+: 401 242 18 ESI+: 391 243 18 ESI+: 379244 18 ESI+: 427 245 18 ESI+: 427 246 18 ESI+: 403 247 18 ESI+: 403 24818 ESI+: 379 249 18 ESI+: 435 250 18 ESI+: 469, 471 251 18 ESI+: 469,471 252 18 ESI+: 453 253 18 ESI+: 391 254 18 ESI+: 453 255 13 ESI+: 459,481([M + Na]⁺) 256 13 ESI+: 317 257 13 ESI+: 401 258 13 ESI+: 403 259 13ESI+: 427 260 13 ESI+: 391 261 13 ESI+: 391 262 13 ESI+: 445, 467([M +Na]⁺) 263 13 ESI+: 485, 507([M + Na]⁺) 264 13 ESI+: 459, 481([M + Na]⁺)265 13 ESI+: 467([M + Na]⁺) 266 13 ESI+: 457 267 13 ESI+: 443 268 13ESI+: 457, 479([M + Na]⁺) 269 13 ESI+: 457 270 13 ESI+: 415, 437([M +Na]⁺) 271 13 ESI+: 445, 467([M + Na]⁺) 272 13 ESI+: 507 273 13 ESI+: 419274 13 ESI+: 479 275 13 ESI+: 493 276 13 ESI+: 323([M-Boc]⁺) 277 13ESI+: 529 278 13 ESI+: 529 279 13 ESI+: 491 280 13 ESI+: 507

TABLE 89 PEx Psyn Dat 281 13 ESI+: 463 282 13 ESI+: 463 283 13 ESI+: 485284 13 ESI+: 385([M-Boc]⁺) 285 13 ESI+: 501 286 13 ESI+: 491 287 13ESI+: 493 288 13 ESI+: 485 289 13 ESI+: 501 290 13 ESI+: 507 291 17ESI+: 389 292 17 ESI+: 387 293 17 ESI+: 373 294 15 ESI+: 537 295 15ESI+: 361, 383([M + Na]⁺) 296 15 ESI+: 375 297 15 ESI+: 447 298 15 ESI+:447 299 15 ESI+: 417 300 15 ESI+: 523 301 15 ESI+: 391 302 20 ESI+: 433,455([M + Na]⁺) 303 20 ESI+: 433 304 20 ESI+: 403 305 20 ESI+: 509 306334 ESI+: 377 307 334 ESI+: 389 308 334 ESI+: 373 309 334 ESI+: 439 310334 ESI+: 443, 445 311 334 ESI+: 391 312 334 ESI+: 465([M + Na]⁺),467([M + Na]⁺) 313 334 ESI+: 465([M + Na]⁺), 467([M + Na]⁺) 314 334ESI+: 461([M + Na]⁺) 315 334 ESI+: 416 316 334 ESI+: 410 317 334 ESI+:439 318 334 ESI+: 437 319 334 ESI+: 359 320 334 ESI+: 405, 427([M +Na]⁺)

TABLE 90 PEx Psyn Dat 321 334 ESI+: 403 322 334 ESI+: 377 323 334 ESI+:405 324 334 ESI+: 403, 425([M + Na]⁺) 325 334 ESI+: 391, 413([M + Na]⁺)326 334 ESI+: 379, 401([M + Na]⁺) 327 334 ESI+: 403 328 334 ESI+: 379,401([M + Na]⁺) 329 334 ESI+: 405.427([M + Na]⁺) 330 334 ESI+: 389 331334 ESI+: 419 332 334 ESI+: 401 333 334 ESI+: 401 334 334 ESI+: 416 335334 ESI+: 391, 413([M + Na]⁺) 336 334 ESI+: 427 337 339 ESI+: 345 338339 ESI+: 359 339 339 ESI+: 407 340 339 ESI+: 361 341 339 ESI+: 389 342339 ESI+: 411, 413 343 339 ESI+: 389 344 344 ESI+: 365, 367 345 345ESI+: 451 346 345 ESI+: 485, 487 347 345 ESI+: 485, 487 348 349 ESI+:485, 487 349 349 ESI+: 481 350 349 ESI+: 481 351 349 ESI+: 453 352 349ESI+: 509([M + Na]⁺), 511([M + Na]⁺) 353 349 ESI+: 509([M + Na]⁺),511([M + Na]⁺) 354 349 ESI+: 509([M + Na]⁺), 511([M + Na]⁺) 355 349ESI+: 483 356 349 ESI+: 483 357 349 ESI+: 471 358 349 ESI+: 471 359 349ESI+: 471 360 349 ESI+: 531, 533

TABLE 91 PEx Psyn Dat 361 349 ESI+: 467 362 349 ESI+: 467 363 367 ESI+:437 364 367 ESI+: 403 365 367 ESI+: 389 366 367 ESI+: 375 367 367 ESI+:411, 413 368 27 ESI+: 448 369 38 ESI+: 451 370 28 ESI+: 350 371 29 ESI+:393 372 30 ESI+: 349 373 31 ESI+: 331 374 37 ESI+: 577 375 375 ESI+: 383376 376 ESI+: 386 377 377 ESI+: 425 378 377 ESI+: 427 379 379 ESI+: 417380 380 ESI+: 331 381 381 NMR-C: 1.19(3H, d, J = 6.6 Hz), 1.28(3H, t, J= 7.1 Hz), 2.75-2.89(4H, m), 3.34-3.44(1H, m), 3.51-3.65(4H, m),3.69(1H, dd, J = 8.7, 7.6 Hz), 3.93(1H, dd, J = 8.7, 4.1 Hz), 4.18(2H,q, J = 7.1 Hz), 6.66(1H, s), 7.28(1H, s) 382 381 ESI+: 371, 373 383 383ESI+: 291 384 383 ESI+: 291 385 385 ESI+: 317 386 386 ESI+: 301 387 387ESI+: 236 388 388 ESI+: 277 389 389 ESI+: 275 390 390 ESI+: 293 391 545ESI+: 587 392 7 ESI+: 374 393 7 ESI+: 371, 373 394 7 ESI+: 327, 329 395408 ESI+: 441, 443 396 408 ESI+: 455 397 408 ESI+: 457 398 408 ESI+:443, 445 399 408 ESI+: 455, 457 400 408 ESI+: 465; 467

TABLE 92 PEx Psyn Dat 401 408 ESI+: 491; 493 402 408 ESI+: 467, 469 403408 ESI+: 455, 457 404 408 ESI+: 443, 445 405 408 ESI+: 467, 469 406 408ESI+: 443, 445 407 408 ESI+: 469, 471 408 408 ESI+: 413 409 409 ESI+:314, 316 410 411 ESI+: 453; 455 411 411 ESI+: 467; 469 412 411 ESI+:355, 357 413 411 ESI+: 437; 439 414 411 ESI+: 455 415 411 ESI+: 529, 531416 411 ESI+: 467, 469 417 411 ESI+: 455, 457 418 411 ESI+: 479, 481 419411 ESI+: 409, 411 420 411 ESI+: 455, 457 421 411 ESI+: 467, 469 422 411ESI+: 467, 469 423 411 ESI+: 479, 481 424 411 ESI+: 479, 481 425 549ESI+: 435 426 426 ESI+: 346 427 427 FAB−: 395, 397 428 427 ESI+: 353,355 429 23 ESI+: 369([M + Na]⁺) 430 23 ESI+: 347, 369([M + Na]⁺) 431 23ESI+: 385([M + Na]⁺) 432 23 ESI+: 361, 383([M + Na]⁺) 433 11 ESI+: 439,441 434 11 NMR-C: 0.44-0.51(2H, m), 0.95(6H, s), 0.97-1.06(2H, m),1.47(9H, s), 1.58-1.68(1H, m), 2.69-2.78(2H, m), 3.04(2H, s),3.06-3.18(4H, m), 3.21(3H, s), 3.29-3.36(2H, m), 3.46-3.58(4H, m),4.15-4.22(2H, m), 6.48(1H, s) 435 11 ESI+: 383, 385 436 11 ESI+: 377 43711 ESI+: 331 438 11 ESI+: 345 439 11 ESI+: 453, 455 440 11 ESI+: 389

TABLE 93 PEx Psyn Dat 441 11 ESI+: 441, 443 442 11 ESI+: 391 443 11ESI+: 465, 467 444 11 ESI+: 387 445 11 ESI+: 389 446 11 ESI+: 339, 341447 11 ESI+: 397, 399 448 11 ESI+: 413 449 11 ESI+: 395, 397 450 11ESI+: 377 451 11 ESI+: 377 452 11 ESI+: 391 453 11 ESI+: 441, 443 454 11ESI+: 389 455 11 ESI+: 377 456 11 ESI+: 365 457 11 ESI+: 453, 455 458 11ESI+: 453, 455 459 11 ESI+: 389 460 11 ESI+: 365 461 11 ESI+: 431 462 11ESI+: 471 463 11 ESI+: 445 464 11 ESI+: 333 465 11 ESI+: 349 466 11ESI+: 347 467 11 ESI+: 391 468 11 ESI+: 405 469 11 ESI+: 347 470 11ESI+: 361 471 11 ESI+: 465, 467 472 11 ESI+: 465 473 11 ESI+: 431 474 11ESI+: 443 475 11 ESI+: 429 476 11 ESI+: 443 477 11 ESI+: 401 478 11ESI+: 443 479 11 ESI+: 465 480 11 ESI+: 493

TABLE 94 PEx Psyn Dat 481 11 ESI+: 431 482 11 ESI+: 405 483 11 ESI+: 479484 11 ESI+: 309([M-Boc]⁺) 485 11 ESI+: 515 486 11 ESI+: 515 487 11ESI+: 477 488 11 ESI+: 493 489 11 ESI+: 449 490 11 ESI+: 449 491 11ESI+: 377 492 11 ESI+: 471 493 11 ESI+: 471 494 11 ESI+: 487, 489 495495 ESI+: 473, 475 496 495 ESI+: 507, 509 497 495 ESI+: 507, 509 498 495EI: 491, 493 499 495 ESI+: 492, 493 500 12 ESI+: 429; 431 501 12 ESI+:425 502 12 ESI+: 413 503 12 ESI+: 420 504 12 ESI+: 463 505 12 ESI+: 409506 19 ESI+: 303 507 19 ESI+: 473 508 19 ESI+: 405 509 19 ESI+: 501 51019 ESI+: 495 511 19 ESI+: 361 512 19 ESI+: 347 513 19 ESI+: 433 514 19ESI+: 393 515 71 ESI+: 345 516 71 ESI+: 319 517 71 ESI+: 331 518 71ESI+: 319 519 162 ESI+: 437, 439 520 162 ESI+: 435, 437

TABLE 95 PEx Psyn Dat 521 18 ESI+: 417 522 18 ESI+: 417 523 13 ESI+: 479524 13 ESI+: 493 525 13 ESI+: 479 526 13 ESI+: 533 527 13 ESI+: 497 52813 ESI+: 513 529 13 ESI+: 493 530 13 ESI+: 485 531 13 ESI+: 485 532 15ESI+: 523 533 15 ESI+: 537 534 15 ESI+: 559 535 15 ESI+: 431 536 20ESI+: 433 537 20 ESI+: 509 538 339 ESI+: 486 539 540 ESI+: 526 540 540ESI+: 538 541 540 ESI+: 467 542 540 ESI+: 467 543 543 ESI+: 531 544 545ESI+: 587 545 545 ESI+: 543 546 545 ESI+: 601 547 408 ESI+: 455, 457 548408 ESI+: 455, 457 549 549 ESI+: 435 550 549 ESI+: 449 551 11 ESI+: 465552 11 ESI+: 477 553 11 ESI+: 479 554 11 ESI+: 471 555 11 ESI+: 487, 489556 11 ESI+: 493 557 11 ESI+: 479 558 11 ESI+: 465 559 11 ESI+: 519 56011 ESI+: 479

TABLE 96 PEx Psyn Dat 561 11 ESI+: 483 562 11 ESI+: 499, 501 563 11ESI+: 471 564 11 ESI+: 471 565 565 ESI+: 527 566 565 ESI+: 527 567 565ESI+: 527 568 565 ESI+: 561, 563 569 565 ESI+: 563 570 565 ESI+: 545 57119 ESI+: 433 572 19 ESI+: 447 573 20 ESI+: 363 574 15 ESI+: 377

TABLE 97 Ex Str 1

2 M

3 M

4

5

6 H

7 M

8 M

TABLE 98 Ex Str  9 M

10 M

11

12 M

13 H

14 M

15

16

TABLE 99 Ex Str 17

18

19 M

20 M

21

22 H

23 H

24 M

TABLE 100 Ex Str 25 H

26 M

27 M

28 H

29

30

31 M

32 M

TABLE 101 Ex Str 33 M

34 M

35 M

36

37 M

38 M

39 M

40 M

TABLE 102 Ex Str 41 M

42 M

43 M

44 M

45 M

46

47 M

TABLE 103 Ex Str 48 M

49 M

50

51

52 M

53 M

54 M

TABLE 104 Ex Str 55 M

56

57

58

59 M

60

61

TABLE 105 Ex Str 62 H

63 M

64

65

66 M

67 M

TABLE 106 Ex Str 68 H

69 H

70 M

71 M

72 M

73 H

TABLE 107 Ex Str 74 M

75 H

76 M

77

78 M

79 M

80 M

TABLE 108 Ex Str 81 M

82 H

83 M

84 M

85 M

86

TABLE 109 Ex Str 87

88 H

89 M

90 M

91 M

92 H

93 M

TABLE 110 Ex Str 94  H

95  M

96 

97  M

98  M

99  M

100

TABLE 111 Ex Str 101 M

102 M

103

104 M

105

106 H

TABLE 112 Ex Str 107 M

108 M

109 M

110 M

111

112 M

TABLE 113 Ex Str 113

114 M

115 M

116 M

117 M

118 H

TABLE 114 Ex Str 119

120 M

121 H

122

123

124

125

TABLE 115 Ex Str 126

127 M

128 M

129 M

130 M

131 M

132 M

TABLE 116 Ex Str 133

134 M

135 M

136 M

137 M

138 M

TABLE 117 Ex Str 139 M

140 M

141 H

142 H

143 H

144 M

TABLE 118 Ex Str 145 M

146 M

147 M

148 M

149

150 H

TABLE 119 Ex Str 151 M

152 H

153 H

154 H

155 M

156 M

157 M

TABLE 120 Ex Str 158 M

159

160 M

161 M

162 M

163 M

TABLE 121 Ex Str 164 M

165

166

167

168

169 M

TABLE 122 Ex Str 170 M

171 M

172 M

173 M

174 H

175

TABLE 123 Ex Str 176

177 M

178 M

179 M

180 M

181 H

TABLE 124 Ex Str 182 H

183 M

184 M

185 M

186 M

TABLE 125 Ex Str 187 M

188 H

189

190

191

192 H

193 H

TABLE 126 Ex Str 194 H

195 M

196 M

197 M

198 M

199 M

TABLE 127 Ex Str 200H

201M

202

203M

204H

205H

TABLE 128 Ex Str 206M

207M

208H

209H

210M

211M

TABLE 129 Ex Str 212M

213M

214H

215

216M

217H

TABLE 130 Ex Str 218H

219H

220H

221M

222H

223H

TABLE 131 Ex Str 224M

225

226

227

228H

229M

230

TABLE 132 Ex Str 231

232H

233H

234M

235M

236M

TABLE 133 Ex Str 237M

238M

239M

240M

241M

242M

243M

TABLE 134 Ex Str 244M

245M

246M

247M

248M

249M

TABLE 135 Ex Str 250

251H

252

253

254S

255H

TABLE 136 Ex Str 256M

257H

258M

259M

260H

261

TABLE 137 Ex Str 262

263H

264

265H

266M

267T

TABLE 138 Ex Str 268M

269H

270M

271M

272M

TABLE 139 Ex Str 273M

274M

275M

276M

277M

TABLE 140 Ex Str 278

279

280M

281M

282M

283H

TABLE 141 Ex Str 284H

285H

286M

287M

288M

TABLE 142 Ex Str 289 H

290 M

291 H

292 M

293 M

294 M

TABLE 143 Ex Str 295 M

296 M

297 M

298 M

299 M

TABLE 144 Ex Str 300 M

301 M

302 M

303 M

304 M

TABLE 145 Ex Str 305 M

306 M

307 M

308 M

TABLE 146 Ex Str 309 M

310 M

311 S

312 H

313 H

TABLE 147 Ex Str 314 M

315 M

316 M

317 M

318

319

TABLE 148 Ex Syn Dat 1 1 ESI+: 251, 253 NMR: 2.44-2.53(3H, m),2.72-2.74(4H, m), 2.79-2.85(4H, m), 3.02-3.04(2H, m), 6.93 (1H, s),9.20(1H, s) mp: 165-167 2 2 ESI+: 293, 295 NMR: 0.96(6H, d, J = 6.5 Hz),1.69-1.75(2H, m), 1.98-2.07(1H, m), 2.67-2.70(4H, m), 2.90-2.95(2H, m),2.97-3.04(6H, m), 3.10-3.65(5H, m), 6.46(2H, s), 6.81(1H, s) mp: 159-1633 3 ESI+: 203 NMR: 1.69-1.81(2H, m), 2.57(2H, t, J = 6.2 Hz),2.75-2.86(4H, m), 2.94-3.06(4H, m), 3.08-3.15(2H, m), 6.23(1H, s),6.44(2H, s), 6.62(1H, s) 4 4 ESI+: 231 NMR: 2.49-2.56(2H, m),2.76-2.83(2H, m), 2.98-3.20(8H, m), 3.23(3H, s), 6.97(1H, s), 7.05(1H,s), 9.14(2H, s) 5 5 ESI+: 315 NMR: 0.22-0.32(1H, m), 0.38-0.49(1H, m),0.97-1.07(2H, m), 1.50-1.70(2H, m), 2.17- 2.30(1H, m), 2.31-2.43(1H, m),2.51-2.61(1H, m), 2.74-3.18(8H, m), 3.30-3.42(1H, m), 3.34(3H, s),3.73(1H, d, J = 14.3 Hz), 4.14(1H, d, J = 14.3 Hz), 4.70-4.81(1H, m),6.85(1H, s) 6 6 ESI+: 275 NMR: 1.23(3H, t, J = 7.1 Hz), 1.78-1.86(2H,m), 2.66(2H, t, J = 6.6 Hz), 2.83-2.91(4H, m), 2.91-2.99(4H, m),3.61-3.67(2H, m), 4.13(2H, q, J = 7.1 Hz), 6.40(1H, s), 6.88(1H, s),7.43(1H, s) mp: 178(decomp.) 7 7 ESI+: 274 NMR: 1.78-1.86(2H, m),2.65(2H, t, J = 6.7 Hz), 2.76-2.86(10H, m), 2.86-2.94(4H, m),3.36-3.41(2H, m), 6.39(1H, s), 6.56(1H, s), 6.83(1H, s) mp: 230(decomp.)8 8 ESI+: 274 NMR: 1.05(3H, t, J = 7.1 Hz), 1.74-1.82(2H, m), 2.62(2H,t, J = 6.5 Hz), 2.89-2.97(4H, m), 3.01-3.15(6H, m), 3.52(2H, m),6.45(2H, s), 6.65(1H, t, J = 5.4 Hz), 6.89(1H, s), 7.25(1H, s) mp:174-176 9 9 ESI+: 295 NMR: 1.20(3H, t, J = 7.3 Hz), 1.85-1.94(2H, m),2.73(2H, t, J = 6.7 Hz), 2.91-3.00(4H, m), 3.00-3.10(4H, m), 3.23(2H, q,J = 7.3 Hz), 3.62-3.69(2H, m), 6.45(2H, s), 6.96(1H, s), 7.30(1H, s) mp:176(decomp.) 10 2 ESI+: 261 NMR: 1.75-1.83(2H, m), 2.55-2.62(2H, m),2.78-2.84(2H, m), 2.84-2.90(2H, m), 2.94- 3.06(4H, m), 3.20-3.28(2H, m),3.26(3H, s), 3.34-3.41(2H, m), 3.44-3.50(2H, m), 6.40 (1H, s), 6.43(2H,s), 6.65(1H, s)

TABLE 149 Ex Syn Dat 11 5 ESI+: 313 NMR: 0.26-0.33(1H, m), 0.36-0.43(1H,m), 0.82(3H, d, J = 6.6 Hz), 0.92-1.05(2H, m), 1.15(3H, d, J = 6.9 Hz),1.48-1.70(2H, m), 2.13-2.29(1H, m), 2.32-2.45(1H, m), 2.50-2.59 (1H, m),2.62-3.13(9H, m), 3.35-3.45(1H, m), 4.67-4.78(1H, m), 6.84(1H, s) 12 2ESI+: 237, 239 NMR: 1.73-1.79(2H, m), 2.64(2H, t, J = 6.2 Hz),2.74-4.34(13H, m), 5.40(1H, s), 6.44(2H, s), 6.67(1H, s) 13 2 ESI+: 251,253 NMR: 1.72-1.78(2H, m), 2.67-2.70(5H, m), 2.85-2.92(6H, m),2.96-2.99(2H, m), 3.13- 3.76(4H, m), 6.40(1H, s), 6.79(1H, s) 14 2 ESI+:219 NMR: 2.78(3H, s), 2.81-2.87(2H, m), 2.87-2.93(2H, m), 2.98-3.09(4H,m), 3.13- 3.19(2H, m), 4.15-4.21(2H, m), 6.44(2H, s), 6.50(1H, s),6.54(1H, s) 15 2 ESI+: 279, 281 NMR: 1.58-3.32(16H, m), 4.05-4.12(0.35H,m), 4.51-4.58(0.65H, m), 7.04(0.35H, s), 7.16(0.65H, s), 9.06-9.18(2H,br) 16 2 ESI+: 265, 267 NMR: 1.19(3H, t, J = 6.9 Hz), 1.68-1.74(2H, m),2.69(2H, t, J = 6.6 Hz), 2.85(2H, q, J = 6.9 Hz), 2.95-2.98(2H, m),3.00-3.02(2H, m), 3.13-3.18(4H, m), 3.29-3.32(2H, m), 6.86(1H, s),9.01-9.20(2H, br) mp: 221-223 17 2 ESI+: 219 NMR: 2.96-3.04(4H, m),3.05-3.14(4H, m), 4.52(2H, s), 6.72(1H, s), 6.82(1H, s), 9.26- 9.42(2H,br), 10.71(1H, s) 18 2 ESI+: 233 NMR: 3.01-3.19(8H, m), 3.25(3H, s),4.61(2H, s), 6.88(1H, s), 7.05(1H, s), 9.33- 9.47(2H, br) 19 2 FAB+: 233NMR: 2.04(3H, s), 2.78(3H, s), 2.85-3.09(8H, br), 3.12-3.23(2H, m),4.17-4.28(2H, m), 6.42(1H, s), 6.44(2H, s) 20 2 FAB+: 205 NMR:2.75-2.89(4H, br), 2.93-3.08(4H, br), 3.15-3.31(2H, m), 3.99-4.13(2H,m), 5.17- 5.93(0.7H, br), 6.36(1H, s), 6.44(1.8H, s), 6.46(1H, s) mp:192-195 21 2 ESI+: 307, 309 NMR: 0.73(3H, d, J = 6.3 Hz), 1.07-1.19(4H,m), 1.54-2.19(2H, m), 2.38-2.75(6H, m), 3.07-3.39(6H, m),4.14-4.27(0.15H, br), 4.49-4.55(0.85H, br), 7.01-7.20(1H, m), 9.00-9.27(2H, br) mp: 245-249 22 2 ESI+: 279, 281 NMR: 0.87(3H, t, J = 7.3Hz), 1.64-1.73(4H, m), 2.65-2.68(2H, m), 2.72-2.76(2H, m), 2.84-2.91(6H,m), 2.96-2.98(2H, m), 3.02-3.70(4H, m), 6.41(1H, s), 6.77(1H, s) 23 2ESI+: 295, 297 NMR: 1.69-1.75(2H, m), 2.67(2H, t, J = 6.4 Hz), 2.85-2.91(6H, m), 2.98(2H, t, J = 6.4 Hz), 3.02-3.04(2H, m), 3.10-3.60(6H, m),3.67(2H, t, J = 6.4 Hz), 6.41(1H, s), 6.78(1H, s)

TABLE 150 Ex Syn Dat 24 2 ESI+: 217 NMR: 1.79-1.90(2H, m), 2.61(2H, t, J= 6.2 Hz), 2.79(3H, s), 2.74-2.93(4H, m), 2.94-3.07 (4H, m),3.07-3.15(2H, m), 6.40(1H, s), 6.43(2H, s), 6.67(1H, s) 25 2 FAB+: 219NMR: 2.02(3H, s), 2.65-2.95(8H, m), 3.15-3.28(2H, m), 4.05-4.14(2H, m),5.32- 5.54(1H, br), 6.21(1H, s), 6.37(1H, s) 26 2 FAB+: 233 NMR:1.04(3H, t, J = 7.0 Hz), 2.78-2.94(4H, br), 2.95-3.08(4H, br),3.15-3.24(2H, m), 3.28(2H, q, J = 7.0 Hz), 4.06-4.18(2H, m), 6.44(2H,s), 6.49(1H, s), 6.55(1H, s) 27 2 FAB+: 283, 285 NMR: 2.81-2.90(2H, m),2.90-3.00(4H, m), 3.11-3.20(2H, m), 3.29-3.37(2H, m), 4.02- 4.10(2H, m),5.31-5.39(1H, br), 6.43(1.3H, s), 6.57(1H, s) 28 2 ESI+: 219 NMR:1.99(3H, s), 2.74-2.83(2H, m), 2.86-2.97(6H, m), 3.24-3.31(2H, m), 3.98-4.06(2H, m), 4.86-5.09(1H, br), 6.37(1H, s), 6.38(1H, s) 29 2 ESI+: 283NMR: 2.97-3.06(4H, m), 3.07-3.18(7H, m), 3.74-3.81(2H, m), 4.20-4.28(2H,m), 6.80 (1H, s), 7.40(1H, s), 9.28-9.42(2H, br) 30 2 ESI+: 247 NMR:1.12(6H, d, J = 6.6 Hz), 2.87-3.14(8H, br), 3.15-3.25(2H, br),4.02-4.20(3H, m), 6.57(1H, s), 6.75(1H, s), 9.31-9.52(2H, br) 31 2 ESI+:233 NMR: 2.19(3H, s), 2.56(3H, s), 2.88-2.94(2H, m), 2.95-3.08(8H, m),4.04-4.11(2H, m), 6.44(2H, s), 6.51(1H, s) 32 2 ESI+: 281, 283 NMR:1.69-1.80(2H, m), 2.64(2H, t, J = 6.2 Hz), 2.80-2.89(2H, m),2.89-3.01(4H, m), 3.13-3.21(2H, m), 3.21-3.29(2H, m), 6.42(1.4H, s),6.69(1H, s) 33 2 ESI+: 245 NMR: 1.78-1.89(2H, m), 2.15(3H, s), 2.64(2H,t, J = 6.6 Hz), 2.88-3.08(8H, m), 3.64(2H, t, J = 6.2 Hz), 6.44(2H, s),6.96(1H, s) mp: 159-162 34 2 ESI+: 231 NMR: 1.03(3H, t, J = 7.0 Hz),1.78-1.87(2H, m), 2.59(2H, t, J = 6.2 Hz), 2.79-2.84(2H, m),2.86-2.92(2H, m), 2.96-3.06(4H, m), 3.16(2H, t, J = 5.5 Hz), 3.28(2H, q,J = 7.0 Hz), 6.41(1H, s), 6.43(2H, s), 6.65(1H, s) 35 2 ESI+: 297, 299NMR: 2.72(3H, s), 2.93-3.12(8H, m), 3.23-3.33(2H, m), 4.08-4.20(2H, m),6.46(2H, s), 6.72(1H, s) mp: 200-204 36 2 ESI+: 245 NMR: 0.50-0.64(2H,m), 0.99-1.12(2H, m), 1.57-1.68(1H, m), 2.90-3.01(2H, m), 3.04- 3.17(4H,m), 3.23-3.34(2H, m), 3.36-3.47(2H, m), 4.20-4.33(2H, br), 6.62(1H, s),9.19- 9.38(2H, br) mp: 193-197

TABLE 151 Ex Syn Dat 37 2 ESI+: 273 NMR: 1.01(6H, d, J = 6.6 Hz),1.78-1.90(2H, m), 2.64(2H, t, J = 6.8 Hz), 2.91-3.14(9H, m), 3.64(2H, t,J = 6.2 Hz), 6.46(2H, s), 7.00(1H, s), 7.09-7.24(1H, br) 38 2 ESI+: 259NMR: 0.89(6H, d, J = 6.5 Hz), 1.76-1.84(2H, m), 1.92-2.04(1H, m),2.60(2H, t, J = 6.3 Hz), 2.77-2.84(2H, m), 2.85-2.91(2H, m), 2.97(2H, d,J = 7.4 Hz), 2.97-3.06(4H, m), 3.16- 3.25(2H, m), 6.33(1H, s), 6.44(2H,s), 6.65(1H, s) 39 2 ESI+: 305, 307 NMR: 0.52-0.98(4H, m), 1.43-2.77(6H,m), 2.89-4.33(11H,), 4.42-4.54(1H, m), 6.48(2H, s), 6.97-7.11(1H, m) 402 ESI+: 319, 321 NMR: 1.39-4.80(24H, m), 6.48(2H, s), 6.99(0.4H, s),7.08(0.6H, s) 41 2 ESI+: 291, 293 NMR: 0.17-0.20(2H, m), 0.47-0.52(2H,m), 1.04-1.15(1H, m), 1.69-1.75(2H, m), 2.67 (2H, t, J = 6.7 Hz),2.74(2H, d, J = 6.4 Hz), 2.85-2.91(6H, m), 3.05-3.80(6H, m), 6.41(1H,s), 6.78(1H, s) 42 2 ESI+: 305, 307 NMR: 1.69-1.92(6H, m), 1.99-2.05(2H,m), 2.65-2.75(3H, m), 2.82-3.95(15H, m), 6.46 (2H, s), 6.80(1H, s) mp:141-143 43 2 ESI+: 333, 335 NMR: 1.18-2.12(10H, m), 2.32-2.75(4H, m),2.92-4.18(11H, m), 4.18-4.29(0.25H, br), 4.48-4.59(0.75H, br), 6.48(2H,s), 6.99(0.25H, s), 7.11(0.75H, s) 44 2 ESI+: 341, 343 NMR:11.68-1.83(1H, br), 2.64-2.82(2H, m), 2.82-4.02(14H, m), 6.48(2H, s),7.08(1H, s), 7.14-7.71(5H, br) 45 2 ESI+: 319, 321 NMR: 1.30-1.38(2H,m), 1.47-1.63(4H, m), 1.70-1.77(4H, m), 2.28(1H, quint, J = 7.5 Hz),2.68(2H, t, J = 6.7 Hz), 2.82(2H, d, J = 7.3 Hz), 2.91-2.94(2H, m),2.99-3.05(6H, m), 3.11-3.71(5H, m), 6.46(2H, s), 6.81(1H, s) mp: 151-15346 2 ESI+: 327, 329 NMR: 1.72-1.78(2H, m), 2.74(2H, t, J = 6.6 Hz),2.81-2.84(2H, m), 3.05-3.07(2H, m), 3.15-3.20(4H, m), 3.32-3.35(2H, m),4.09(2H, s), 6.93(1H, s), 7.28(1H, t, J = 7.4 Hz), 7.37(2H, t, J = 7.4Hz), 7.54(2H, d, J = 7.4 Hz), 9.0-9.30(2H, br) 47 2 ESI+: 347, 348 NMR:0.73-3.85(26H, m), 4.13-4.24(0.2H, br), 4.46-4.55(0.8H, br), 6.45(1H,s), 6.93- 7.00(0.2H, br), 7.08(0.8H, s) 48 2 ESI+: 333, 335 NMR:0.94-1.04(2H, m), 1.13-1.27(3H, m), 1.62-1.75(6H, m), 1.83(2H, d, J =12.8 Hz), 2.66-2.72(4H,m), 2.91-2.94(2H, m), 2.99-3.03(6H, m),3.11-3.74(5H, m), 6.46(2H, s), 6.81(1H, s) 49 2 ESI+: 217 NMR:1.69-1.79(2H, m), 1.95(3H, s), 2.61(2H, t, J = 6.2 Hz), 2.79-2.87(2H,m), 2.93-3.05 (6H, m), 3.21(2H, t, J = 5.3 Hz), 6.44(2H, s), 6.54(1H, s)

TABLE 152 Ex Syn Dat 50 2 ESI+: 219 NMR: 1.33(3H, d, J = 6.4 Hz),2.91-3.22(9H, m), 3.44-3.54(1H, m), 4.26-4.37(1H, m), 6.75(1H, s),6.87(1H, s), 9.36-9.58(2H, br) mp: 193-194 51 2 ESI+: 279 NMR:1.79-1.97(2H, m), 2.58-2.69(2H, m), 2.69-2.80(2H, m), 2.93-3.08(4H, m),3.08- 3.23(4H, m), 6.95(1H, s), 7.15-7.29(2H, m), 7.37-7.56(3H, m),9.11-9.33(2H, m) 52 2 FAB+; 231 NMR: 1.67-1.79(2H, m), 2.18(3H, s),2.53(3H, s), 2.66(2H, t, J = 6.6 Hz), 2.85-2.93(2H, m), 2.93-3.06(8H,m), 6.43(2H, s), 6.67(1H, s) 53 2 ESI+: 263 NMR: 2.80-2.94(4H, m),2.96-3.09(4H, m), 3.26(3H, s), 3.29-3.34(2H, m), 3.38(2H, t, J = 5.4Hz), 3.50(2H, t, J = 5.4 Hz), 4.04-4.12(2H, m), 6.44(1.8H, s), 6.50(1H,s), 6.54(1H, s) 54 2 ESI+: 233 NMR-A: 1.26(3H, d, J = 6.3 Hz),2.74-2.98(8H, m), 3.06-3.18(4H, br), 3.19-3.26(1H, m), 4.18-4.28(1H, m),6.54(1H, s), 6.56(1H, s), 6.64(1H, s), 8.65-8.98(2H, br) 55 2 ESI+: 261NMR: 1.05(3H, d, J = 6.5 Hz), 1.12(3H, d, J = 6.5 Hz), 1.26(3H, d, J =6.2 Hz), 2.63-2.73(1H, m), 2.76-3.12(8H, m), 3.19-3.30(1H, m),3.98-4.13(2H, m), 6.44(1.7H, s), 6.50(1H, s), 6.62(1H, s) 56 2 ESI+: 259NMR: 0.18-0.32(2H, m), 0.41-0.57(2H, m), 0.92-1.08(1H, m),2.83-3.22(10H, m), 3.30- 3.48(2H, m), 4.10-4.24(2H, m), 6.57(1H, s),6.73(1H, s), 9.27-9.55(2H, br) mp: 179-182 57 2 ESI+: 275 NMR: 1.06(6H,d, J = 6.6 Hz), 2.94-3.04(4H, m), 3.08-3.19(5H, m), 3.80-3.90(2H, m),4.16-4.28(2H, m), 6.76(1H, s), 7.25-7.86(1H, br), 9.10-9.36(2H, br) 58 2ESI+: 261 NMR: 0.90(6H, d, J = 6.7 Hz), 1.91-2.05(1H, m), 2.82-2.99(6H,m), 3.05-3.15(4H, br), 3.24-3.30(2H, m), 4.07-4.12(2H, m), 6.50(1H, s),6.52(1H, s), 8.80-8.96(2H, br) mp: 157 59 2 ESI+: 277 NMR: 1.68-1.80(2H,m), 2.77-2.92(4H, m), 2.96-3.09(4H, m), 3.17-3.30(7H, m), 3.36 (2H, t, J= 6.1 Hz), 4.05-4.15(2H, m), 6.44(2H, s), 6.49(1H, s), 6.51(1H, s) mp:141-145 60 1 ESI+: 337 NMR: 1.70-1.80(2H, m), 2.36-2.42(2H, m),2.66-2.80(4H, m), 2.86-2.93(2H, m), 2.97- 3.07(4H, m), 3.02(3H, s),3.11-3.17(2H, m), 3.21-3.28(2H, m), 6.82(1H, s), 7.07-7.13(2H, m),7.28-7.34(1H, m), 7.36-7.42(2H, m) 61 2 ESI+: 261 NMR: 0.92(3H, t, J =7.3 Hz), 1.26-1.40(2H, m), 1.45-1.58(2H, m), 2.85-3.14(8H, m),3.16-3.34(4H, m), 4.08-4.23(2H, m), 6.54(1H, s), 6.60(1H, s),9.30-9.54(2H, br) 62 2 ESI+: 295 NMR: 2.70-2.97(8H, m), 3.22-3.31(2H,m), 4.10-4.20(2H, m), 4.42(2H, s), 6.39(1H, s), 6.51(1H, s), 6.55(1H,s), 7.21-7.40(5H, m)

TABLE 153 Ex Syn Dat 63 2 ESI+: 277 NMR: 1.10(3H, t, J = 6.9 Hz),2.78-2.95(4H, m), 2.97-3.10(4H, m), 3.29-3.48(6H, m), 3.53 (2H, t, J =5.7 Hz), 4.04-4.12(2H, m), 6.44(1.8H, s), 6.50(1H, s), 6.55(1H, s) 64 2ESI+: 303 NMR: 1.17-1.32(2H, m), 1.52-1.64(2H, br), 1.85-2.00(1H, m),2.81-3.18(10H, m), 3.21- 3.36(4H, m), 3.79-3.92(2H, m), 4.02-4.17(2H,m), 6.51(1H, s), 6.54(1H, s), 9.30-9.52(2H, br) 65 2 ESI+: 281 NMR:2.59-2.70(2H, m), 2.90-3.17(6H, m), 3.20-3.32(2H, m), 4.14-4.24(2H, m),6.73(1H, s), 7.19-7.30(2H, m), 7.39-7.54(3H, m), 9.29-9.49(2H, br) 66 2ESI+: 309 NMR: 1.66-1.78(2H, m), 2.51-2.58(2H, m), 2.61-2.70(2H, m),2.82-2.95(4H, m), 2.97- 3.12(4H, m), 3.76(3H, s), 6.43(2H, s), 6.65(1H,d, J = 2.0 Hz), 6.67(1H, d, J = 7.7 Hz), 6.72(1H, s), 6.94(1H, dd, J =2.0, 7.8 Hz), 7.38(1H, dd, J = 7.7, 7.8 Hz) 67 2 ESI+: 313, 315 NMR:1.64-1.80(2H, m), 2.46-2.56(2H, m), 2.66(2H, t, J = 6.2 Hz),2.79-2.93(3H, m), 2.94- 3.02(2H, m), 3.03-3.13(2H, m), 3.88-3.99(1H,br), 6.40(1.5H, s), 6.73(1H, s), 7.03-7.10 (1H, m), 7.12-7.16(1H, m),7.40-7.46(1H, m), 7.49(1H, dd, J = 7.6, 7.9 Hz) mp: 159-162 68 2 ESI+:347, 349 NMR: 1.66-1.78(2H, m), 2.41-2.47(2H, m), 2.65(2H, t, J = 6.2Hz), 2.72-2.84(4H, m), 2.84- 2.94(2H, m), 3.01-3.11(2H, m),4.08-4.15(1H, br), 6.37(1H, s), 6.71(1H, s), 7.07(1H, dd, J = 1.8, 8.2Hz), 7.32(1H, d, J = 1.8 Hz), 7.68(1H, d, J = 8.2 Hz) 69 2 ESI+: 371,373 NMR: 1.62-1.73(2H, m), 2.38-2.45(2H, m), 2.52-2.65(4H, m),2.66-2.73(2H, m), 2.74- 2.83(2H, m), 2.84-2.99(6H, m), 2.95(3H, s),6.38(1H, s), 6.84(1H, s), 7.07-7.12(1H, m), 7.17-7.21(1H, m),7.38-7.50(2H, m) 70 2 ESI+: 405, 407 NMR: 1.61-1.73(2H, m),2.39-2.74(8H, m), 2.77-2.99(8H, m), 2.96(3H, s), 6.40(0.8H, s), 6.87(1H,s), 7.13(1H, dd), 7.41(1H, d, J = 1.8 Hz), 7.70(1H, d, J = 8.2 Hz) 71 2ESI+: 275 NMR: 2.47-2.53(2H, m), 2.71-2.80(2H, m), 2.88-3.08(8H, m),3.24(3H, s), 3.48(2H, t, J = 6.1 Hz), 4.02(2H, t, J = 6.1 Hz),6.44(1.7H, s), 6.99(1H, s), 7.01(1H, s) mp: 164-166 72 2 ESI+: 365 NMR:0.34(3H, d, J = 6.8 Hz), 0.35(3H, d, J = 6.8 Hz), 1.13-1.29(1H, m),1.58-1.78(2H, m), 2.18-2.36(2H, m), 2.56-2.66(2H, m), 2.71(2H, t, J =6.6 Hz), 2.81-3.09(8H, m), 3.74(3H, s), 6.42(2H, s), 6.63-6.73(2H, m),6.85(1H, s), 6.88(1H, dd, J = 1.8, 7.8 Hz), 7.30(1H, dd, J = 7.7, 7.8Hz) 73 2 ESI+: 367 NMR: 1.61-1.73(2H, m), 2.30-2.50(4H, m),2.53-2.60(2H, m), 2.60-2.73(4H, m), 2.73-2.81(2H, m), 2.82-2.97(4H, m),2.93(3H, s), 3.75(3H, s), 6.37(1H, s), 6.66-6.70(2H, m), 6.80 (1H, s),6.88-6.93(1H, m), 7.33(1H, dd, J = 7.9, 8.2 Hz) 74 2 ESI+: 243 NMR:0.23-0.33(2H, m), 0.98-1.08(2H, m), 1.29-1.39(1H, m), 1.70-1.81(2H, m),2.60(2H, t, J = 6.2 Hz), 2.76-2.85(2H, m), 2.92-3.08(4H, m),3.13-3.23(2H, m), 3.23-3.29(2H, m), 4.97(1H, s), 6.42(2H, s), 6.57(1H,s)

TABLE 154 Ex Syn Dat 75 2 ESI+: 355 NMR: 1.70-1.81(2H, m), 2.47-2.53(2H,m), 2.61-2.66(2H, m), 2.66-2.74(2H, m), 2.79 (2H, t, J = 6.6 Hz),2.82-2.89(2H, m), 2.90-3.05(6H, m), 3.04(3H, s), 6.47(1H, s), 6.92(1H,s), 7.01-7.10(2H, m), 7.21-7.31(1H, m), 7.51-7.60(1H, dd, J = 7.1, 14.4Hz) 76 2 ESI+: 291 NMR: 1.07(6H, d, J = 6.1 Hz), 2.79-2.94(4H, m),2.96-3.10(4H, m), 3.28-3.41(4H, m), 3.48- 3.59(3H, m), 4.04-4.13(2H, m),6.44(1.8H, s), 6.50(1H, s), 6.54(1H, s) mp: 135 77 2 ESI+: 289 NMR:1.51-1.64(1H, m), 1.92-2.04(1H, m), 2.54-2.65(1H, m), 2.84-3.35(12H, m),3.38- 3.49(1H, m), 3.58-3.68(1H, m), 3.69-3.84(2H, m), 4.06-4.15(2H, m),6.53(1H, s), 6.59(1H, s), 9.28-9.54(2H, br) 78 2 ESI+: 353 NMR: 2.34(3H,s), 2.39-2.48(2H, m), 2.54-2.65(4H, m), 2.77-3.09(11H, m), 3.96-4.08(2H, m), 6.40(1.5H, s), 6.67(1H, s), 6.93(1H, d, J = 7.6 Hz), 6.98(1H,s), 7.18(1H, d, J = 7.6 Hz), 7.33(1H, t, J = 7.6 Hz) mp: 173-176 79 2ESI+: 295 NMR: 2.35(3H, s), 2.52-2.61(2H, m), 2.81-2.97(4H, m),2.97-3.12(2H, m), 3.12-3.25(2H, m), 3.92-4.12(3H, m), 6.42(1.8H, s),6.57(1H, s), 6.92(1H, d, J = 7.7 Hz), 6.95(1H, s), 7.19(1H, d, J = 7.7Hz), 7.36(1H, t, J = 7.7 Hz) 80 2 ESI+: 299 NMR: 0.29-0.38(2H, m),0.81(6H, d, J = 6.7 Hz), 0.89-1.00(2H, m), 1.54-1.66(1H, m), 1.66-1.77(2H, m), 1.84-1.99(1H, m), 2.58(2H, t, J = 6.3 Hz), 2.78-2.85(2H,m), 2.92(2H, d, J = 7.3 Hz), 2.94-3.05(4H, m), 3.07-3.17(2H, m),3.17-3.25(2H, m), 6.40(1H, s), 6.62(1H, s) 81 2 ESI+: 301 NMR:0.30-0.42(2H, m), 0.93-1.04(2H, m), 1.57-1.74(3H, m), 2.61(2H, t, J =6.4 Hz), 2.83- 2.94(2H, m), 2.98-3.32(13H, m), 3.56(2H, t, J = 6.2 Hz),6.43(2H, s), 6.65(1H, s) 82 2 ESI+: 291 NMR: 1.29(3H, d, J = 7.3 Hz),2.73(1H, dd, J = 12.0, 7.3 Hz), 2.80-3.00(5H, m), 3.11-3.18 (1H, m),3.25(3H, s), 3.53(2H, t, J = 5.6 Hz), 4.01-4.12(2H, m), 4.58(2H, s),6.44(1H, s), 6.79(1H, s), 7.04(1H, s) 83 2 ESI+: 305 NMR: 1.32(3H, d, J= 7.4 Hz), 1.79(2H, quint, J = 6.6 Hz), 2.80(1H, dd, J = 13.0, 7.4 Hz),2.85-3.09(5H, m), 3.20-3.28(4H, m), 3.36(2H, t, J = 6.6 Hz), 3.94(2H, t,J = 6.6 Hz), 4.57(2H, s), 6.48(2H, s), 6.83(1H, s), 6.96(1H, s) 84 2ESI+: 277 NMR: 1.27(3H, d, J = 7.2 Hz), 2.77-2.88(4H, m), 3.02-3.14(3H,m), 3.26(3H, s), 3.31- 3.33(2H, m), 3.38-3.41(2H, m), 3.51(2H, t, J =5.5 Hz), 4.07-4.09(2H, m), 6.45(2H, s), 6.48(1H, s), 6.51(1H, s) 85 2ESI+: 291 NMR: 1.28(3H, d, J = 7.2 Hz), 1.74(2H, quint, J = 6.3 Hz),2.76-2.89(4H, m), 3.04-3.16(3H, m), 3.22-3.29(7H, m), 3.37(2H, t, J =6.3 Hz), 4.10-4.12(2H, m), 6.45(2H, s), 6.48(1H, s), 6.50(1H, s)

TABLE 155 Ex Syn Dat 86 2 ESI+: 289 NMR: 1.53-1.62(2H, br),1.62-1.77(2H, m), 2.84-3.15(8H, m), 3.16-3.26(2H, m), 3.45 (2H, t, J =11.2 Hz), 3.80-3.97(3H, m), 4.05-4.14(2H, m), 6.54(1H, s), 6.75(1H, s),9.24- 9.48(1.8H, br) 87 2 ESI+: 245 NMR: 1.31(6H, d, J = 7.1 Hz),1.83-1.95(2H, m), 2.68-2.80(2H, m), 2.97-3.27(8H, m), 3.27-3.45(3H, m),6.94(1H, s), 9.27(2H, s) 88 2 ESI+: 303 NMR: 0.41-0.48(2H, m),0.96-1.03(2H, m), 1.56-1.64(1H, m), 2.75-2.85(2H, m), 2.85- 2.97(4H, m),3.08-3.18(6H, m), 3.25(3H, s), 3.62(2H, t, J = 6.0 Hz), 3.97-4.03(2H,m), 6.38(1H, s), 6.47(1H, s) 89 2 ESI+: 303 NMR: 1.23(6H, d, J = 7.1Hz), 1.65-1.81(2H, m), 2.63-2.70(2H, m), 2.76-2.91(4H, m), 2.93-3.15(8H,m), 3.29(3H, s), 3.58(2H, t, J = 6.2 Hz), 3.85-3.99(1H, m), 6.43(2H, s),6.68(1H, s) 90 2 ESI+: 277 NMR: 2.18(3H, s), 2.80-2.86(2H, m),2.87-2.93(2H, m), 2.94-3.10(8H, m), 3.30(3H, s), 3.61(2H, t, J = 5.8Hz), 4.02-4.08(2H, m), 6.42(1.7H, s), 6.49(1H, s) mp: 166-170 91 2 ESI+:273 NMR: 1.46-1.84(8H, m), 2.79-2.94(4H, m), 2.95-3.07(4H, m),3.12-3.19(2H, m), 4.08- 4.22(3H, m), 6.43(1.7H, s), 6.49(1H, s),6.67(1H, s) 92 2 ESI+: 281 NMR: 2.66-2.74(2H, m), 2.77-2.97(6H, m),3.60-3.70(2H, m), 4.15-4.22(2H, m), 6.38 (1H, s), 6.62-6.66(2H, br),7.02-7.09(1H, m), 7.18-7.25(2H, m), 7.31-7.39(2H, m) mp: 220-222 93 2ESI+: 317 NMR: 0.43-0.49(1H, m), 0.61-0.66(1H, m), 0.98-1.05(2H, m),1.28(3H, d, J = 7.4 Hz), 1.60- 1.67(1H, m), 2.61-2.67(2H, m),2.90-2.93(1H, m), 3.04-3.25(8H, m), 3.32(2H, dd, J = 13.2, 4.8 Hz),3.62(2H, t, J = 5.9 Hz), 3.97-4.03(2H, m), 4.14-4.20(1H, m),6.44-6.46(3H, m) 94 2 ESI+: 275 NMR: 1.67-1.73(2H, m), 2.15(3H, s),2.64(2H, t, J = 6.7 Hz), 2.79-2.84(4H, m), 2.88-2.93 (6H, m),3.02-3.04(2H, m), 3.28(3H, s), 3.59(2H, t, J = 6.2 Hz), 6.37(1H, s),6.62(1H, s) 95 2 ESI+: 261 NMR: 1.67-1.73(2H, m), 2.17(3H, s), 2.65(2H,t, J = 6.7 Hz), 2.72(2H, t, J = 6.7 Hz), 2.89- 2.91(2H, m),2.99-3.04(8H, m), 3.66(2H, t, J = 6.7 Hz), 6.43(2H, s), 6.66(1H, s) 96 2ESI+: 231 NMR: 1.08(3H, t, J = 7.3 Hz), 1.88-1.98(2H, m), 2.62-2.79(4H,m), 2.98-3.18(8H, m), 3.27-3.37(2H, m), 6.92(1H, s), 9.33(2H, s) 97 2ESI+: 289 NMR: 1.03(3H, t, J = 7.4 Hz), 1.68-1.78(2H, m), 2.66(2H, t, J= 6.9 Hz), 2.72(2H, q, J = 7.4 Hz), 2.86(2H, t, J = 6.3 Hz),2.90-2.95(2H, m), 2.95-3.05(4H, m), 3.06-3.13(4H, m), 3.30(3H, s),3.59(2H, t, J = 6.3 Hz), 6.52(2H, s), 6.69(1H, s)

TABLE 156 Ex Syn Dat 98 2 ESI+: 291 NMR: 1.04(3H, t, J = 7.4 Hz),2.71(2H, q, J = 7.4 Hz), 2.84-2.93(4H, m), 2.94-3.08(8H, m), 3.31(3H,s), 3.61(2H, t, J = 5.9 Hz), 4.06-4.12(2H, m), 6.44(2H, s), 6.50(1H, s)mp: 159-163 99 2 ESI+: 277 NMR: 1.07(3H, d, J = 6.7 Hz), 2.79-2.94(4H,m), 2.97-3.09(4H, m), 3.14-3.22(2H, m), 3.24(3H, s), 3.32-3.39(1H, m),3.41-3.48(1H, m), 4.01-4.11(3H, m), 6.44(2H, s), 6.50(1H, s), 6.63(1H,s) 100 2 ESI+: 259 NMR: 0.88(6H, d, J = 6.6 Hz), 1.77-1.98(3H, m),2.54-2.78(4H, m), 2.91-3.17(8H, m), 3.26-3.33(2H, m), 6.88(1H, s),9.34(2H, s) 101 2 ESI+: 305 NMR: 1.24(6H, d, J = 7.4 Hz), 2.80-2.92(4H,m), 2.98-3.13(8H, m), 3.30(3H, s), 3.60(2H, t, J = 5.9 Hz),3.80-3.97(1H, m), 4.04-4.12(2H, m), 6.43(1.8H, s), 6.51(1H, s) 102 2ESI+: 319 NMR: 1.01(3H, t, J = 7.2 Hz), 1.62-1.87(2H, m), 2.62-2.82(6H,m), 2.85-3.07(8H, m), 3.16- 3.28(2H, m), 3.26(3H, s), 3.30(2H, d, J =5.5 Hz), 3.91-3.99(1H, m), 6.43(2H, s), 6.67(1H, s) 103 2 ESI+: 265 NMR:1.83-1.98(2H, m), 2.85-3.00(4H, m), 3.01-3.14(4H, br), 3.22-3.29(2H, m),3.29- 3.37(2H, m), 4.09-4.18(2H, m), 4.53(2H, dt, J = 47.4, 5.8 Hz),6.54(1H, s), 6.57(1H, s), 9.30-9.46(2H, br) 104 2 ESI+: 317 NMR:0.40-0.50(2H, m), 0.96-1.05(2H, m), 1.10(3H, t, J = 7.0 Hz),1.58-1.67(1H, m), 2.84-2.92(2H, m), 2.99-3.18(8H, m), 3.18-3.27(2H, m),3.43(2H, q, J = 7.0 Hz), 3.65(2H, t, J = 6.0 Hz), 3.98-4.05(2H, m),6.44(1.8H, s), 6.52(1H, s) mp: 140-145 105 2 ESI+: 343 NMR:0.35-0.56(6H, m), 0.97-1.08(2H, m), 1.64-1.75(1H, m), 2.90-2.98(2H, m),3.00- 3.36(15H, m), 4.04-4.13(2H, m), 6.54(1H, s), 9.24-9.38(1.8H, br)mp: 166-167 106 2 ESI+: 317 NMR: 0.39-0.47(2H, m), 0.95-1.03(2H, m),1.56-1.65(1H, m), 1.82-1.92(2H, m), 2.78- 2.85(2H, m), 2.87-3.00(6H, m),3.02-3.08(2H, m), 3.13-3.23(5H, m), 3.34(2H, t, J = 6.2 Hz),3.95-4.01(2H, m), 6.37(1H, s), 6.48(1H, s) mp: 169-171 107 2 ESI+: 351NMR: 1.29(3H, d, J = 7.2 Hz), 1.84(2H, quint, J = 6.3 Hz), 2.70(2H, t, J= 6.3 Hz), 2.72-2.88 (3H, m), 2.97-3.23(4H, m), 3.69(2H, t, J = 6.3 Hz),5.17(2H, s), 6.47(2H, s), 6.92(1H, s), 7.31-7.42(5H, m), 7.45(1H, s) 1082 ESI+: 289 NMR: 1.06-1.23(3H, br), 161-1.74(1H, br), 1.96-2.08(4H, br),2.62-2.70(1H, m), 2.91- 3.13(7H, m), 3.16-3.27(2H, m), 3.52-4.29(7H, m),6.87(1H, s) mp: 185-186

TABLE 157 Ex Syn Dat 109 2 ESI+: 288 NMR: 0.98(3H, t, J = 7.1 Hz),1.73-1.84(2H, br), 2.05(3H, s), 2.56(2H, t, J = 6.8 Hz), 2.99- 3.08(6H,m), 3.11-3.18(4H, m), 3.29-4.63(5H, br), 5.88-6.09(1H, br), 6.87(1H, s)mp: 170-171 110 112 ESI+: 293 NMR: 1.82-1.95(2H, m), 2.61-2.71(2H, m),2.74-2.87(4H, m), 2.91-3.07(4H, m), 3.22- 3.32(2H, m), 4.45(2H, s),6.36(1H, s), 6.42(2H, s), 6.70(1H, s), 7.17-7.37(5H, m) mp: 148(decomp.)111 112 ESI+: 325 NMR: 2.85-2.94(4H, m), 3.00-3.12(4H, m), 3.24-3.28(2H,m), 3.73(3H, s), 4.12-4.19(2H, m), 4.41(2H, s), 6.56(1H, s), 6.60(1H,s), 6.79-6.89(3H, m), 7.22-7.28(1H, m), 9.23- 9.44(2H, br) 112 112 ESI+:329, 331 NMR: 2.78-2.88(4H, m), 2.96-3.08(4H, m), 3.27-3.34(2H, m),4.12-4.21(2H, m), 4.44 (2H, s), 6.47(2H, s), 6.54(1H, s), 6.56(1H, s),7.23-7.42(4H, m) mp: 151(decomp.) 113 112 ESI+: 325 NMR: 2.85-2.96(4H,m), 3.01-3.11(4H, m), 3.20-3.27(2H, m), 3.73(3H, s), 4.11-4.17(2H, m),4.36(2H, s), 6.55(1H, s), 6.66(1H, s), 6.87-6.92(2H, m), 7.20-7.27(2H,m), 9.30- 9.49(2H, br) 114 112 ESI+: 329, 331 NMR: 2.28(4H, s),2.72-2.82(4H, m), 2.92-3.04(4H, m), 3.24-3.33(2H, m), 4.10-4.20(2H, m),4.42(2H, s), 6.52(1H, s), 6.54(1H, s), 7.29-7.35(2H, m), 7.37-7.42(2H,m) mp: 178(decomp.) 115 112 ESI+: 325 NMR: 2.28(4H, s), 2.73-2.88(4H,m), 2.94-3.05(4H, m), 3.37-3.46(2H, m), 3.63(2H, t, J = 5.6 Hz),4.07-4.18(4H, m), 6.51(1H, s), 6.61(1H, s), 6.89-6.98(3H, m),7.23-7.33(2H, m) mp: 132-134 116 112 ESI+: 296 NMR: 2.73-2.86(4H, m),2.90-3.04(4H, m), 3.40-3.48(2H, m), 4.14-4.22(2H, m), 4.52 (2H, s),6.43(2H, s), 6.46(1H, s), 6.54(1H, s), 7.23-7.35(2H, m), 7.70-7.79(1H,m), 8.50- 8.57(1H, m) 117 112 ESI+: 302 NMR: 2.78-2.90(4H, m),2.95-3.06(4H, m), 3.38-3.45(2H, m), 4.11-4.17(2H, m), 4.57 (2H, s),6.44(2H, s), 6.51(1H, s), 6.66(1H, s), 7.53(1H, d, J = 2 Hz), 9.06(1H,d, J = 2 Hz) mp: 134-138 118 2 ESI+: 339 NMR-A: 2.41-2.47(2H, m),2.54-2.67(4H, m), 2.94(3H, s), 2.96-3.03(6H, m), 3.13-3.20 (2H, m),4.00-4.07(2H, m), 6.63(1H, s), 6.74(1H, s), 7.15-7.21(2H, m),7.36-7.42(1H, m), 7.44-7.50(2H, m) mp: 199-201

TABLE 158 Ex Syn Dat 119 2 ESI+: 249 NMR: 2.85-2.98(4H, m),3.03-3.12(4H, m), 3.29(2H, t, J = 6.1 Hz), 3.32-3.38(2H, m), 3.57(2H, t,J = 6.1 Hz), 4.02-4.17(2H, m), 5.33-5.89(2H, br), 6.52(1H, s), 6.56(1H,s), 9.17- 9.42(2H, br) 120 2 ESI+: 303 NMR: 0.35-0.39(2H, m),0.97-1.01(2H, m), 1.59-1.72(3H, m), 1.90-2.03(2H, m), 2.27 (4H, s),2.61(2H, t, J = 6.4 Hz), 2.82-2.84(2H, m), 3.00-3.03(2H, m),3.05-3.09(6H, m), 3.19-3.22(2H, m), 4.40(1H, t, J = 5.8 Hz), 4.52(1H, t,J = 5.8 Hz), 6.66(1H, s) 121 2 ESI+: 353, 355 NMR: 2.42-2.48(2H, m),2.69-2.76(2H, m), 2.92-3.01(6H, m), 3.03(3H, s), 3.23-3.35(4H, m),4.19(2H, t, J = 5.4 Hz), 6.42(1H, s), 7.09(m, s) mp: 99-104 122 2 ESI+:337 NMR: 1.78-1.88(2H, m), 2.67(2H, t, J = 6.5 Hz), 2.95-3.05(4H, m),3.08-3.17(4H, m), 3.66- 3.73(2H, m), 5.17(2H, s), 6.95(1H, s),7.28-7.44(5H, m), 7.50(1H, s), 9.20-9.43(2H, br) mp: 185-188 123 2 ESI+:303 NMR: 0.92(6H, d, J = 6.8 Hz), 1.77-1.97(3H, m), 2.68(2H, t, J = 6.5Hz), 2.95-3.04(4H, m), 3.10-3.18(4H, m), 3.63-3.70(2H, m), 3.90(2H, d, J= 6.4 Hz), 6.96(1H, s), 7.48(1H, s), 9.06- 9.26(2H, br) mp: 202-207 1242 ESI+: 245 NMR: 1.12(3H, t, J = 7.0 Hz), 2.46-2.52(2H, m),2.72-2.82(2H, m), 3.00-3.24(8H, m), 3.88(2H, q, J = 7.0 Hz), 6.99(1H,s), 7.04(1H, s), 9.26-9.50(2H, br) mp: 241(decomp.) 125 2 ESI+: 259 NMR:0.87(3H, t, J = 7.4 Hz), 1.47-1.61(2H, m), 2.46-2.52(2H, m),2.73-2.82(2H, m), 3.00- 3.21(8H, m), 3.81(2H, t, J = 7.5 Hz), 6.98(1H,s), 7.04(1H, s), 9.23-9.49(2H, br) mp: 125-129 126 2 ESI+: 307 NMR:2.61-2.70(2H, m), 2.82-3.16(10H, m), 5.11(2H, s), 6.83(1H, s), 7.06(1H,s), 7.18- 7.35(5H, m), 9.21-9.40(2H, br) mp: 177-180 127 2 ESI+: 273NMR: 0.83(6H, d, J = 6.7 Hz), 1.84-1.97(1H, m), 2.30(4H, s),2.45-2.54(2H, m), 2.73- 2.81(2H, m), 2.86-3.07(8H, m), 3.72-3.80(2H, m),6.96(1H, s), 7.01(1H, s) mp: 142-144

TABLE 159 Ex Syn Dat 128 2 ESI+: 289 NMR: 1.24(6H, d, J = 6.2 Hz),1.78-1.84(2H, m), 2.29(4H, s), 2.66(2H, t, J = 6.5 Hz), 2.87- 2.89(4H,br), 2.99-3.01(4H, br), 3.61-3.64(2H, m), 4.87(1H, quint, J = 6.2 Hz),6.90(1H, s), 7.44(1H, s) 129 2 ESI+: 367, 369 NMR: 1.52-1.67(2H, m),2.38-2.47(2H, m), 2.71-2.82(2H, m), 3.01-3.10(9H, m), 3.15 (2H, t, J = 6Hz), 3.30-3.39(2H, m), 4.06(2H, t, J = 7.1 Hz), 6.47(2H, s), 7.13(1H, s)mp: 153-155 130 2 ESI+: 331 NMR: 2.93-3.10(10H, m), 3.13-3.21(2H, m),3.24(3H, s), 3.58(2H, t, J = 5.9 Hz), 4.12(2H, t, J = 4.4 Hz), 6.46(2H,s), 6.91(1H, s) mp: 180(decomp.) 131 2 ESI+: 329 NMR: 1.66-1.81(2H, m),2.68(2H, t, J = 6.4 Hz), 2.90-3.18(12H, m), 3.20(3H, s), 3.52(2H, t, J =6.0 Hz), 6.45(2H, s), 7.02(1H, s) mp: 175(decomp.) 132 2 ESI+: 261 NMR:0.88(3H, t, J = 7.4 Hz), 1.49-1.63(2H, m), 2.86-3.07(8H, m),3.77-3.88(2H, m), 4.57(2H, s), 6.43(2H, s), 6.84(1H, s), 7.03(1H, s) mp:183(decomp.) 133 2 ESI+: 309 NMR: 2.89-3.18(8H, m), 3.32(3H, s),4.75(2H, s), 5.12(2H, s), 6.90(1H, s), 6.94(1H, s), 7.21-7.36(5H, m),9.19-9.37(2H, br) mp: 233(decomp.) 134 2 ESI+: 351 NMR: 1.74-1.80(2H,m), 2.30(4H, s), 2.64(2H, t, J = 6.6 Hz), 2.76-2.79(2H, br),2.84-2.87(2H, br), 2.93-2.99(6H, m), 3.57-3.60(2H, m), 4.33(2H, t, J =6.6 Hz), 6.88(1H, s), 7.21- 7.33(6H, m) 135 2 ESI+: 341, 343 NMR-A:2.98-3.05(4H, m), 3.07-3.13(2H, m), 3.14-3.23(4H, m), 3.28-3.35(5H, m),3.74(2H, t, J = 6.18 Hz), 4.10-4.16(2H, m), 6.64(2H, s), 6.77(1H, s),8.89(2H, s) mp: 183(decomp.) 136 2 ESI+: 337, 339 NMR: 0.70(3H, t, J =7.4 Hz), 1.29-1.45(2H, m), 2.41-2.48(2H, m), 2.72-2.80(2H, m), 3.00-3.11(6H, m), 3.28-3.40(2H, m), 3.98(2H, t, J = 7.3 Hz), 6.47(2H, s),6.98(1H, s) mp: 187(decomp.) 137 2 ESI+: 335 NMR: 0.46(3H, t, J = 7.4Hz), 0.91-1.03(2H, m), 2.30(4H, s), 2.45-2.52(2H, m), 2.71-2.84 (6H, m),2.89-3.11(6H, m), 7.13(1H, s), 7.16-7.23(2H, m), 7.38-7.52(3H, m) mp:196-200

TABLE 160 Ex Syn Dat 138 2 ESI+: 339 NMR: 2.28(3H, s), 2.74-2.96(8H, m),3.72(3H, s), 4.73(2H, s), 5.08(2H, s), 6.79- 6.89(5H, m), 7.18-7.29(1H,m) mp: 188-189 139 2 ESI+: 343, 345 NMR: 2.29(3H, s), 2.74-2.98(8H, m),4.75(2H, s), 5.12(2H, s), 6.83-6.89(2H, m), 7.21-7.26(1H, m),7.30-7.40(3H, m) mp: 192-194 140 2 ESI+: 299 NMR: 0.25-0.36(2H, m),0.66(3H, t, J = 7.4 Hz), 0.95-1.04(2H, m), 1.24-1.36(2H, m),1.81-1.99(1H, m), 2.27-2.45(8H, m), 2.60-2.74(2H, m), 2.87-3.87(8H, m),6.94(1H, s) mp: 170-171 141 2 ESI+: 305 NMR: 0.37-0.50(2H, m),0.95-1.04(2H, m), 1.57-1.67(1H, m), 1.95-2.11(2H, m), 2.78- 2.85(2H, m),2.86-3.03(6H, m), 3.03-3.10(2H, m), 3.11-3.21(2H, m), 3.99(2H, t, J =4.3 Hz), 4.50(2H, dt, J = 47.5, 5.8 Hz), 6.37(1H, s), 6.49(1H, s) mp:144-147 142 2 ESI+: 245 NMR: 0.33-0.42(2H, m), 0.81-0.95(2H, m),1.38-1.48(1H, m), 2.70-2.79(2H, m), 2.84- 2.98(4H, m), 3.05-3.15(2H, m),3.17-3.26(2H, m), 4.03-4.11(2H, m), 5.32-5.62(1H, br), 6.24(1H, s),6.36(1H, s) 143 2 ESI+: 286 NMR: 1.71-1.77(2H, m), 2.29(2H, s), 2.64(2H,t, J = 6.4 Hz), 2.79-2.85(4H, m), 2.90-2.92 (2H, m), 3.04-3.07(2H, m),3.14-3.17(2H, m), 3.27(3H, s), 3.38(2H, t, J = 6.3 Hz), 3.69(2H, t, J =6.3 Hz), 7.02(1H, s) 144 2 ESI+: 339 NMR: 2.30(4H, s), 2.78-2.99(8H, m),3.71(3H, s), 4.71(2H, m), 5.04(2H, s), 6.84(1H, s), 6.85-6.91(2H, m),6.92(1H, s), 7.19-7.24(2H, m) mp: 173-176 145 2 ESI+: 343, 345 NMR:2.81-3.03(8H, m), 4.74(2H, s), 5.11(2H, s), 6.44(2H, s), 6.86(IH, s),6.88(1H, s), 7.27-7.34(2H, m), 7.36-7.43(2H, m) mp: 207(decomp.) 146 2ESI+: 343, 345 NMR: 2.28(3H, s), 2.71-2.96(8H, m), 4.77(2H, s), 5.11(2H,s), 6.86(1H, s), 6.88(1H, s), 7.04-7.09(1H, m), 7.24-7.35(2H, m),7.50-7.54(1H, m) mp: 119-127

TABLE 161 Ex Syn Dat 147 2 ESI+: 385, 387 NMR: 1.74-1.80(2H, m),2.30(4H, s), 2.64(2H, t, J = 6.5 Hz), 2.78-2.81(2H, br), 2.85- 2.87(2H,br), 2.96-2.99(4H, br), 3.09(2H, t, J = 6.5 Hz), 3.57-3.60(2H, m),4.36(2H, t, J = 6.5 Hz), 6.88(1H, s), 7.26-7.33(3H, m), 7.39-7.46(2H, m)mp: 187-188 148 2 ESI+: 337 NMR: 1.78-1.94(2H, m), 2.65(2H, t, J = 7.6Hz), 2.89-3.12(8H, m), 3.87(2H, t, J = 7.5 Hz), 4.58(2H, s), 6.46(2H,s), 6.85(1H, s), 6.87(1H, s), 7.15-7.35(5H, m) mp: 218(decomp.) 149 2ESI+: 339 NMR: 2.97-3.20(8H, m), 4.12-4.32(4H, m), 4.62(2H, s),6.83-6.98(4H, m), 7.18-7.34(3H, m), 9.22-9.41(2H, br) mp: 246(decomp.)150 2 ESI+: 291 NMR: 1.39(3H, d, J = 6.7 Hz), 2.83-3.07(8H, m), 3.24(3H,s), 3.46-3.55(2H, m), 3.97- 4.10(2H, m), 4.63(1H, q, J = 6.7 Hz),6.41(1H, s), 6.82(1H, s), 7.06(1H, s) mp: 189(decomp.) 151 2 ESI+: 273NMR: 0.42-0.50(2H, m), 0.96-1.05(2H, m), 1.17(3H, t, J = 7.0 Hz),1.61-1.70(1H, m), 2.85-2.99(4H, m), 3.00-3.13(6H, m), 3.19-3.28(2H, m),3.94-4.01(2H, m), 6.45(2H, s), 6.53(1H, s) mp: 174-177 152 2 ESI+: 287NMR: 0.41-0.48(2H, m), 0.86(3H, t, J = 7.4 Hz), 0.95-1.03(2H, m),1.57-1.72(3H, m), 2.76- 2.88(4H, m), 2.88-2.98(4H, m), 3.02-3.09(2H, m),3.11-3.20(2H, m), 3.95-4.01(2H, m), 6.37(1H, s), 6.47(1H, s) mp: 138-141153 2 ESI+: 289 NMR: 0.39-0.47(2H, m), 0.94-1.03(2H, m), 1.55-1.65(1H,m), 2.77-2.84(2H, m), 2.87- 2.99(4H, m), 3.03(2H, t, J = 6.5 Hz),3.10-3.20(4H, m), 3.69(2H, t, J = 6.5 Hz), 3.97- 4.05(2H, m), 6.37(1H,s), 6.47(1H, s) mp: 146-150 154 2 ESI+: 277 NMR: 1.23(3H, d, J = 6.3Hz), 2.75-2.81(2H, m), 2.81-2.87(2H, m), 2.90-3.03(5H, m), 3.25(3H, s),3.28-3.37(2H, m), 3.38-3.55(3H, m), 4.02-4.12(1H, m), 6.39(1H, s),6.48(1H, s), 6.51(1H, s) mp: 170(decomp.) 155 2 ESI+: 329, 331 NMR:2.75-2.87(4H, m), 2.91-3.06(4H, m), 3.30-3.38(2H, m), 4.16-4.24(2H, m),4.48 (2H, s), 6.36(1H, s), 6.43(2H, s), 6.57(1H, s), 7.26-7.35(3H, m),7.45-7.52(1H, m) mp: 184(decomp.)

TABLE 162 Ex Syn Dat 156 2 ESI+: 317 NMR: 0.17-0.26(1H, m),0.59-0.69(1H, m), 0.93-1.07(2H, m), 1.23(3H, d, J = 6.1 Hz),1.58-1.69(1H, m), 2.52-2.58(1H, m), 2.75-2.87(1H, m), 2.89-3.05(3H, m),3.05-3.21(5H, m), 3.25(3H, s), 3.29-3.43(2H, m), 3.54-3.67(2H, m),3.96-4.07(1H, m), 6.44(2H, s), 6.51(1H, s) mp: 102-103 157 2 ESI+: 259NMR: 0.49-0.56(2H, m), 0.96-1.05(2H, m), 1.62-1.71(1H, m), 2.77(3H, s),2.85-2.93(2H, m), 2.99-3.12(6H, m), 320-3.28(2H, m), 3.97-4.03(2H, m),6.43(2H, s), 6.53(1H, s) mp: 211(decomp.) 158 2 ESI+: 353, 355 NMR:1.07-1.29(3H, br), 1.62-1.77(1H, br), 1.95-2.11(1H, br), 2.63-2.77(2H,br), 2.86- 3.42(9H, m), 3.94-4.27(3H, m), 7.08(1H, s) mp: 187-189 159 2ESI+: 231 NMR: 1.27(6H, s), 1.84-1.91(2H, m), 3.05-3.20(8H, m),3.26-3.32(2H, m), 6.99(1H, s), 7.37(1H, s), 9.36-9.59(1.9H, br) mp:288-290 160 2 ESI+: 429, 431 NMR: 1.60-2.08(2H, m), 2.65-3.38(12H, m),3.93-4.41(4H, m), 6.94-7.39(6H, m) mp: 176-177 161 2 ESI+: 245 NMR:1.19(6H, s), 1.64-1.70(2H, m), 2.81(3H, s), 2.86-2.94(4H, m),2.99-3.15(6H, m), 6.39(1H, s), 6.44(1.8H, s), 6.93(1H, s) mp: 197-200162 2 ESI+: 385, 387 NMR: 1.74-1.81(2H, m), 2.64(2H, t, J = 6.6 Hz),2.81-2.83(2H, br), 2.88-2.90(2H, br), 2.95- 3.01(6H, m), 3.57-3.60(2H,m), 4.34(2H, t, J = 6.4 Hz), 6.45(2H, s), 6.89(1H, s), 7.23-7.36(5H, m)mp: 201(decomp.) 163 2 ESI+: 381 NMR: 1.74-1.81(2H, m), 2.64(2H, t, J =6.6 Hz), 2.82-2.84(2H, br), 2.89-2.94(4H, m), 2.98- 3.02(4H, br),3.57-3.60(2H, m), 3.78(3H, s), 4.28(2H, t, J = 6.6 Hz), 6.45(2H, s),6.86-6.90(2H, m), 6.98(1H, d, J = 7.9 Hz), 7.16-7.19(1H, m),7.21-7.25(1H, m), 7.30(1H, br) mp: 190(decomp.) 164 2 ESI+: 381 MMR:1.75-1.81(2H, m), 2.64(2H, t, J = 6.6 Hz), 2.81-2.83(2H, br),2.89-2.93(4H, m), 2.98-3.02(4H, br), 3.58-3.61(2H, m), 3.72(3H, s),4.33(2H, t, J = 6.5 Hz), 6.45(2H, s), 6.79-6.84(3H, m), 6.89(1H, s),7.22(1H, t, J = 8.1 Hz), 7.26(1H, br) mp: 196(decomp.)

TABLE 163 Ex Syn Dat 165 2 ESI+: 325 NMR: 2.81-2.94(4H, m),2.97-3.11(4H, m), 3.28-3.37(2H, m), 3.83(3H, s), 4.09-4.20(2H, m),4.37(2H, s), 6.45(1H, s), 6.56(1H, s), 6.85-6.93(1H, m), 7.00-7.06(1H,m), 7.11-7.16(1H, m), 7.21-7.30(1H, m), 9.12-9.41(2H, br). 166 2 ESI+:313 NMR: 2.81-2.94(4H, m), 2.98-3.15(4H, m), 3.22-3.38(2H, m),4.09-4.24(2H, m), 4.46 (2H, s), 6.55(1H, s), 6.57(1H, s), 7.01-7.20(3H,m), 7.32-7.45(1H, m), 9.13-9.41(2H, br) 167 2 ESI+: 309 NMR: 2.29(3H,s), 2.84-2.95(4H, m), 2.99-3.11(4H, m), 3.23-3.31(2H, m), 4.11-4.19(2H,m), 4.39(2H, s), 6.56(1H, s), 6.60(1H, s), 7.05-7.14(3H, m), 7.22(1H, t,J = 7.5 Hz), 9.28-9.54(2H, br) 168 2 ESI+: 320 NMR: 2.83-2.95(4H, m),2.99-3.13(4H, m), 3.28-3.37(2H, m), 4.14-4.24(2H, m), 4.49 (2H, s),6.54(1H, s), 6.58(1H, s), 7.52-7.60(1H, m), 7.63-7.69(1H, m),7.71-7.80(2H, m), 9.17-9.53(2H, br) 169 2 ESI+: 363 NMR: 2.76-2.88(4H,m), 2.94-3.07(4H, m), 3.2-3.34(2H, m), 4.13-4.21(2H, m), 4.53(2H, s),6.44(2H, s), 6.56(1H, s), 6.58(1H, s), 7.54-7.70(4H, m) mp: 141-146 1702 ESI+: 289 NMR: 1.18(6H, s), 1.58-1.64(2H, m), 2.85-2.93(4H, m),3.00-3.10(4H, m), 3.24-3.30(5H, m), 3.37-3.45(2H, m), 3.46-3.52(2H, m),6.40(1H, s), 6.44(2H, s), 6.92(1H, s) mp: 172-175 171 2 ESI+: 385, 387NMR: 1.74-1.81(2H, m), 2.64(2H, t, J = 6.5 Hz), 2.81-2.83(2H, br),2.89-2.92(2H, br), 2.95(2H, t, J = 6.4 Hz), 2.99-3.03(4H, br),3.57-3.60(2H, m), 4.33(2H, t, J = 6.4 Hz), 6.45(2H, s), 6.89(1H, s),7.22(1H, br), 7.30(2H, d, J = 8.5 Hz), 7.37(2H, d, J = 8.5 Hz) 172 2ESI+: 353 NMR: 2.29(4H, s), 2.73-2.75(2H, br), 2.81-2.83(2H, m),2.93-2.98(6H, m), 3.74(2H, t, J = 4.5 Hz), 4.14(2H, t, J = 4.5 Hz),4.37(2H, t, J = 6.5 Hz), 6.67(1H, s), 7.21-7.34(5H, m), 7.36-7.44(1H,br) mp: 185-187 173 2 ESl+: 387, 389 NMR: 2.30(4H, s), 2.73-2.75(2H,br), 2.82-2.84(2H, br), 2.94-2.98(6H, m), 3.73(2H, t, J = 4.5 Hz),4.14(2H, t, J = 4.5 Hz), 4.37(2H, t, J = 6.4 Hz), 6.67(1H, s),7.30-7.38(5H, m) mp: 186(decomp.) 174 2 ESI+: 357 NMR: 2.52-3.04(17H,m), 3.97-4.12(2H, m), 6.36(1H, s), 6.71(1H, s), 7.16-7.24(1H, m),7.26-7.34(2H, m), 7.41-7.50(1H, m) mp: 179-182

TABLE 164 Ex Syn Dat 175 2 ESI+: 355, 357 NMR: 3.13-3.21(6H, m),3.23(3H, s), 3.30-3.37(2H, m), 3.52(2H, t, J = 5.7 Hz), 4.09(2H, t, J =5.7 Hz), 4.73(2H, s), 7.22(1H, s), 9.19-9.38(2H, br) mp: 244(decomp.)176 2 ESI+: 341, 343 NMR: 3.00-3.06(2H, m), 3.07-3.15(4H, m),3.21-3.27(5H, m), 3.35-3.40(2H, m), 3.42- 3.53(4H, m), 4.10-4.24(2H, m),6.64(1H, s), 9.20-9.42(2H, br) mp: 107-110 177 2 ESI+: 387, 389 NMR:2.30(4H, s), 2.75-2.77(2H, br), 2.81-2.83(2H, br), 2.93-2.97(4H, br),3.11(2H, t, J = 6.4 Hz), 3.74(2H, t, J = 4.5 Hz), 4.14(2H, t, J = 4.5Hz), 4.40(2H, t, J = 6.4 Hz), 6.67(1H, s), 7.26-7.33(2H, m),7.41-7.46(3H, m) mp: 169-170 178 2 ESI+: 387, 389 NMR: 2.30(4H, s),2.74-2.76(2H, br), 2.81-2.84(2H, br), 2.93-3.00(6H, m), 3.74(2H, t, J =4.5 Hz), 4.14(2H, t, J = 4.5 Hz), 4.39(2H, t, J = 6.4 Hz), 6.67(1H, s),7.25-7.38(5H, m) mp: 160-162 179 2 ESI+: 383 NMR: 2.30(4H, s),2.75-2.77(2H, br), 2.81-2.84(2H, br), 2.92-2.98(6H, m), 3.73(2H, t, J =4.5 Hz), 3.78(3H, s), 4.14(2H, t, J = 4.5 Hz), 4.32(2H, t, J = 6.6 Hz),6.67(1H, s), 6.87-6.90 (1H, m), 6.97-6.99(1H, m), 7.18-7.25(2H, m),7.39-7.51(1H, br) mp: 158-160 180 2 ESI+: 383 NMR: 2.30(4H, s),2.73-2.75(2H, br), 2.81-2.84(2H, br), 2.92-2.98(6H, m), 3.72(3H, s),3.74(2H, t, J = 4.5 Hz), 4.14(2H, t, J = 4.5 Hz), 4.37(2H, t, J = 6.5Hz), 6.67(1H, s), 6.79-6.82 (1H, m), 6.84-6.86(2H, m), 7.22(1H, t, J =8.1 Hz), 7.35-7.44(1H, br) mp: 134-136 181 2 ESI+: 317 NMR: 1.41(3H, s),1.88(3H, s), 2.61-3.16(12H, m), 3.25(3H, s), 3.37-3.52(2H; m), 3.92-4.09(2H, m), 5.06(1H, s), 6.38(1H, s), 6.55(1H, s) mp: 173-176 182 2ESI+: 367 NMR: 2.57-2.68(2H, m), 2.83-3.10(14H, m), 3.26(3H, s),3.58(2H, t, J = 5.8 Hz), 4.11- 4.14(2H, m), 6.44(1H, s), 6.54(1H, s),7.15-7.34(5H, m) 183 2 ESI+: 305 NMR: 0.96(3H, t, J = 7.7 Hz),1.28-1.45(2H, m), 2.58-2.68(2H, m), 2.78-3.09(12H, m), 3.31(3H, s),3.61(2H, t, J = 6.3 Hz), 4.03-4.21(2H, m), 6.40(1H, s), 6.48(1H, s) 1842 ESI+: 339 NMR: 2.52-2.60(2H, m), 2.85-2.99(4H, m), 3.03-3.10(2H, m),3.28(3H, s), 3.29-3.35(2H, m), 3.41-3.58(4H, m), 3.92-4.01(2H, m),6.42(2H, s), 6.62(1H, s), 7.05-7.14(2H, m), 7.27-7.33(1H, m),7.35-7.41(2H, m) mp: 169(decomp.)

TABLE 165 Ex Syn Dat 185 2 ESI+: 371 NMR: 2.30(4H, s), 2.75-2.77(2H,br), 2.81-2.84(2H, br), 2.94-2.98(4H, br), 3.01(2H, t, J = 6.4 Hz),3.73(2H, t, J = 4.5 Hz), 4.14(2H, t, J = 4.5 Hz), 4.37(2H, t, J = 6.4Hz), 6.67(1H, s), 7.14-7.20(2H, m), 7.27-7.33(1H, m), 7.36-7.47(2H, m)mp: 186-187 186 2 ESI+: 371 NMR: 2.30(4H, s), 2.73-2.75(2H, br),2.81-2.83(2H, br), 2.93-2.98(4H, br), 3.00(2H, t, J = 6.4 Hz), 3.73(2H,t, J = 4.5 Hz), 4.14(2H, t, J = 4.5 Hz), 4.39(2H, t, J = 6.4 Hz),6.67(1H, s), 7.03-7.08(1H, m), 7.12-7.17(2H, m), 7.32-7.43(2H, m) mp:162-164 187 2 ESI+: 371 NMR: 2.30(4H, s), 2.74-2.76(2H, br),2.82-2.84(2H, br), 2.94-2.98(6H, m), 3.74(2H, t, J = 4.5 Hz), 4.14(2H,t, J = 4.5 Hz), 4.36(2H, t, J = 6.5 Hz), 6.67(1H, s), 7.10-7.16(2H, m),7.29-7.35(2H, m), 7.35-7.44(1H, br) mp: 179-181 188 2 ESI+: 305 NMR:1.36(6H, s), 2.81-3.02(8H, m), 3.24(3H, s), 3.50(2H, t, J = 6.0 Hz),4.04(2H, t, J = 5.9 Hz), 6.40(1H, s), 6.78(1H, s), 7.02(1H, s) mp:175-176 189 2 ESI+: 287 NMR: 2.85-3.00(4H, m), 3.04-3.15(4H, m),3.37-3.48(2H, m), 4.03-4.20(4H, m), 6.59 (1H, s), 6.73(1H, s),9.09-9.33(2H, br) mp: 221-222 190 2 ESR: 365, 367 NMR: 3.04-3.19(8H, m),3.33-3.39(2H, m), 3.72(2H, q, J = 9.3 Hz), 4.20-4.27(2H, m), 6.81(1H,s), 9.17-9.38(2H, br) mp: 214-215 191 2 ESI+: 365, 367 NMR:2.99-3.17(6H, m), 3.21-3.29(2H, m), 3.46(2H, t, J = 4.2 Hz),4.13-4.26(4H, m), 6.83(1H, s), 9.10-9.33(2H, br) mp: 216-221 192 2 ESI+:345 NMR-A: 2.57-2.68(6H, m), 2.95-3.22(11H, m), 4.00-4.08(2H, m),6.63(1H, s), 6.72(1H, s), 6.98(1H, dd, J = 4.9, 1.2 Hz), 7.33(1H, dd, J= 2.8, 1.2 Hz), 7.66(1H, dd, J = 4.9, 2.8 Hz) mp: 200(decomp.) 193 2ESI+: 345 NMR: 2.65-2.79(6H, m), 2.94-3.22(11H, m), 4.02-4.10(2H, m),6.64(1H, s), 6.78(1H, s), 6.97(1H, dd, J = 3.5, 1.2 Hz), 7.18(1H, dd, J= 5.3, 3.5 Hz), 7.69(1H, dd, J = 5.3, 1.2 Hz) mp: 200(decomp.)

TABLE 166 Ex Syn Dat 194 2 ESI+: 327 NMR: 0.35-0.43(2H, m),0.86-0.96(2H, m), 1.40-1.52(1H, m), 2.77-2.86(2H, m), 2.86- 2.98(4H, m),3.05-3.18(2H, m), 3.36-3.42(2H, m), 4.00-4.16(4H, m), 6.37(1H, s), 6.57(1H, s) mp: 177(decomp.) 195 2 ESI+: 289 NMR: 1.16(6H, s), 1.66(2H, t, J= 6.6 Hz), 2.61(2H,t, J = 6.6 Hz), 2.81-2.95(4H, m), 2.98- 3.10(4H, m),3.30(3H, s), 3.31-3.37(2H, m), 3.38-3.44(2H, m), 6.35(1H, s), 6.44(1.8H,s), 6.71(1H, s) mp: 156-158 196 2 ESI+: 367 NMR: 1.26(3H, d, J = 7.0Hz), 2.30(4H, s), 2.71-2.72(2H, br), 2.81-2.83(2H, m), 2.93- 2.97(4H,m), 3.10-3.19(1H, m), 3.69-3.71(2H, m), 4.09-4.12(2H, m), 4.26(2H, d, J= 7.1 Hz), 6.66(1H, s), 7.21-7.35(6H, m) mp: 177-179 197 2 ESI+: 367NMR: 1.26(3H, d, J = 6.3 Hz), 2.29(4H, s), 2.80-2.85(4H, m), 2.91(2H, d,J = 6.4 Hz), 2.96- 2.98(4H, m), 3.64-3.69(1H, m), 3.77-3.83(1H, m),3.99-4.04(1H, m), 4.12-4.17(1H, m), 5.00-5.08(1H, m), 6.67(1H, s),7.19-7.23(3H, m), 7.27-7.31(2H, m), 7.48(1H, brs) mp: 85-87 198 2 ESI+:431, 433 NMR: 2.31(4H, s), 2.79-2.82(2H, m), 2.91-2.99(6H, m),3.15-3.18(2H, m), 3.76(2H, t, J = 4.4 Hz), 4.26(2H, t, J = 4.4 Hz),4.39(2H, t, J = 6.5 Hz), 7.21-7.33(5H, m), 7.39-7.45(1H, br) mp: 142-143199 2 ESI+: 297, 299 NMR: 2.29(4H, s), 2.85-2.88(2H, m), 2.95-2.99(4H,m), 3.02-3.05(2H, m), 3.25(3H, s), 3.35-3.38(2H, m), 3.41-3.44(2H, m),3.49-3.51(2H, m), 4.16-4.18(2H, m), 6.56(1H, s) mp: 139-141 200 2 ESI+:311, 313 NMR: 1.26(3H, t, J = 7.1 Hz), 2.28(2H, s), 2.86-2.91(6H, m),3.08-3.11(2H, m), 3.82-3.84 (2H, m), 4.18(2H, q, J = 7.1 Hz),4.29-4.31(2H, m), 7.61(1H, brs); mp: 145-147 201 2 ESI+: 393 NMR:0.38-0.43(2H, m), 0.92-0.97(2H, m), 1.46-1.53(1H, m), 2.28(4H, s),2.74-2.77(2H, m), 2.94-2.97(4H, m), 3.01-3.03(2H, m), 3.17-3.19(2H, m),3.70-3.72(2H, m), 4.16- 4.18(2H, m), 4.36(2H, t, J = 6.5 Hz),7.21-7.34(6H, m) mp: 142-144

TABLE 167 Ex Syn Dat 202 2 ESI+: 313 NMR: 2.84-2.99(4H, m),3.02-3.15(4H, m), 3.34-3.40(5H, m), 3.56-3.76(4H, m), 4.03- 4.14(2H, m),6.57(1H, s), 6.63(1H, s), 9.06-9.25(2H, br) mp: 172-173 203 2 ESI+: 353NMR: 0.35-0.46(2H, m), 0.97-1.06(2H, m), 1.59-1.70(1H, m), 2.83-2.91(2H,m), 2.96- 3.10(4H, m), 3.16-3.23(5H, m), 3.24-3.31(2H, m), 3.51(2H, t, J= 13.3 Hz), 3.70(2H, t, J = 16 Hz), 4.08-4.16(2H, m), 6.43(2H, s),6.52(1H, s) mp: 163-165 204 2 ESI+: 291 NMR: 1.20(6H, s), 2.71-2.77(2H,m), 2.78-2.84(2H, m), 2.87-2.96(4H, m), 3.05(2H, s), 3.25(3H, s),3.39-3.45(2H, m), 3.47-3.53(2H, m), 6.37(1H, s), 6.44(1H, s), 6.50(1H,s) mp: 194(decomp.) 205 2 ESI+: 283 NMR-A: 1.81-2.00(2H, m),2.46-2.63(3H, br), 2.75-2.90(4H, m), 2.97-3.26(8H, m), 6.48- 6.59(1H,br), 6.63(1H, s), 6.98-7.13(1H, br), 7.63-7.78(1H, br), 7.82-7.94(1H,br) mp: 203(decomp.) 206 2 ESI+: 277 NMR: 1.07(3H, d, J = 6.5 Hz),2.79-2.91(4H, m), 2.98-3.07(4H, m), 3.25-3.34(4H, m), 3.40-3.54(4H, m),3.86(1H, dd, J = 10.4, 2.3 Hz), 3.93(1H, dd, J = 10.4, 3.1 Hz),6.43(1.8H, s), 6.50(1H, s), 6.53(1H, s) mp: 133-136 207 2 ESI+: 277 NMR:1.07(3H, d, J = 6.5 Hz), 2.79-2.93(4H, m), 2.98-3.07(4H, m),3.25-3.34(4H, m), 3.39-3.54(4H, m), 3.86(1H, dd, J = 10.4, 2.3 Hz),3.93(1H, dd, J = 10.4, 3.0 Hz), 6.44(1.8H, s), 6.50(1H, s), 6.53(1H, s)mp. 131-134 208 2 ESI+: 429 NMR: 2.26(2H, s), 2.49-2.53(2H, m),2.77-2.79(4H, m), 2.89-2.91(2H, m), 2.98(2H, t, J = 6.5 Hz),3.70-3.72(2H, m), 4.01-4.03(2H, m), 4.39(2H, t, J = 6.5 Hz),7.08-7.11(2H, m), 7.22-7.35(6H, m), 7.37-7.41(3H, m) mp: 169-171 209 2ESI+: 283 NMR: 1.68-1.83(2H, m), 2.03(3H, s), 2.33-2.42(2H, m), 2.71(2H,t, J = 6.4 Hz), 2.93-3.10 (6H, m), 3.11-3.24(2H, m), 6.50(1H, t, J = 2.1Hz), 6.63(1H, s), 7.00(1H, s), 8.65-8.95(2H, m) mp: 206(decomp.)

TABLE 168 Ex Syn Dat 210 2 ESI+: 285 NMR: 2.33(3H, s), 2.82-2.89(2H, m),2.95-3.12(6H, m), 3.12-3.22(2H, m), 4.07-4.13(2H, m), 6.51-6.52(1H, m),6.64(1H, s), 6.75(1H, s), 7.63-7.65(1H, m), 7.81(1H, t, J = 1.7 Hz),8.66-8.91(2H, br) mp: 226(decomp.) 211 2 ESI+: 327 NMR: 0.35-0.48(2H,m), 0.97-1.08(2H, m), 1.64-1.78(1H, m), 2.84-2.94(2H, m), 2.98- 3.11(4H,m), 3.17-3.30(4H, m), 3.93(2H, q, J = 10 Hz), 4.12(2H, t, J = 4.5 Hz),6.44(2H, s), 6.55(1H, s) mp: 174(decomp.) 212 2 ESI+: 395 NMR: 0.90(3H,t, J = 7.3 Hz), 1.30-1.39(2H, m), 2.53-2.57(2H, m), 2.80-2.82(2H, m),2.95- 3.01(8H, m), 3.71-3.73(2H, m), 4.16-4.18(2H, m), 4.37(2H, t, J =6.5 Hz), 6.45(2H, s), 7.21-7.34(6H, m) mp: 134-136 213 2 ESI+: 401 NMR:0.87-0.97(5H, m), 1.10-1.25(3H, m), 1.31-1.41(3H, m), 1.53(2H, q, J =6.6 Hz), 1.59- 1.71(5H, m), 2.55-2.59(2H, m), 2.88-2.91(2H, m),2.95-3.02(6H, m), 3.76-3.78(2H, m), 4.16(2H, t, J = 6.6 Hz),4.20-4.22(2H, m), 6.44(2H, s), 7.46(1H, brs) mp: 139-141 214 2 ESI+: 435NMR: 2.63-2.66(2H, m), 2.77-2.82(4H, m), 2.88-2.91(2H, m), 2.96-2.99(2H,m), 3.71- 3.73(2H, m), 4.07-4.09(2H, m), 4.39(2H, t, J = 6.5 Hz),6.40(1H, s), 6.84(1H, dd, J = 3.4, 1.1 Hz), 7.10(1H, dd, J = 5.2, 3.4Hz), 7.21-7.34(5H, m), 7.40-7.47(1H, br), 7.59(1H, dd, J = 5.2, 1.1 Hz)mp: 215-216 215 2 ESI+: 329 NMR: 0.32-0.39(1H, m), 0.54-0.62(1H, m),0.96-1.07(2H, m), 1.33-1.44(1H, m), 1.58- 1.67(1H, m), 1.69-1.85(2H, m),1.91-2.01(1H, m), 2.86-3.38(11H, m), 3.46-3.55(1H, m), 3.60-3.69(1H, m),3.72-3.80(1H, m), 3.94-4.18(3H, m), 6.53(1H, s), 9.18-9.44(2H, br) mp:154-156 216 2 ESI+: 317 NMR: 0.32-0.41(1H, m), 0.48-0.57(1H, m),0.96-1.10(5H, m), 1.55-1.65(1H, m), 2.81- 3.30(14H, m), 3.34-3.42(1H,m), 3.64-3.73(1H, m), 3.96-4.08(2H, m), 6.43(2H, s), 6.50 (1H, s) mp:135-138 217 2 ESI+: 305 NMR: 0.31-0.41(1H, m), 0.46-0.57(1H, m),0.95-1.04(2H, m), 1.27(3H, dd, J = 23.9, 6.3 Hz), 1.55-1.65(1H, m),2.74-3.02(6H, m), 3.04-3.31(6H, m), 3.97-4.09(2H, m), 4.96- 5.22(1H, m),6.37(1H, s), 6.49(1H, s) mp: 171-173

TABLE 169 Ex Syn Dat 218 2 ESI+: 301 NMR-A: 2.24(3H, s), 2.76-2.85(2H,m), 2.93-3.11(6H, m), 3.12-3.23(2H, br), 4.03- 4.11(2H, m), 6.63(1H, s),6.79(1H, s), 6.98(1H, dd, J = 3.4, 1.1 Hz), 7.16(1H, dd, J = 5.1, 3.5Hz), 7.68(1H, dd, J = 5.1, 1.1 Hz), 8.71-8.96(2H, br) mp: 248-252 219 2ESI+: 295 NMR-A: 2.09(3H, s), 2.63-2.71(2H, m), 2.95-3.09(6H, m),3.14-3.23(2H, br), 4.04- 4.11(2H, m), 6.64(1H, s), 6.76(1H, s),7.19-7.24(2H, m), 7.34-7.40(1H, m), 7.43-7.49(2H, m), 6.80(2H, s) mp:250(decomp.) 220 2 ESI+: 341, 343 NMR: 1.69-1.75(2H, m), 2.04-2.17(2H,m), 2.27(2H, s), 2.70(2H, t, J = 6.7 Hz), 2.85-2.91 (8H, m),2.96-2.99(2H, m), 3.20-3.22(2H, m), 4.46(1H, t, J = 5.9 Hz), 4.58(1H, t,J = 5.9 Hz), 6.83(1H, s) 221 2 ESI+: 317 NMR: 0.29-0.35(2H, br),0.98-1.05(2H, br), 1.62-1.75(2H, m), 1.86-1.93(1H, m), 2.29 (4H, s),2.36-2.39(2H, m), 2.65-2.69(2H, m), 2.90-2.94(2H, br), 3.01-3.10(4H,br), 3.21- 3.28(2H, br), 4.06-4.29(2H, br), 4.23(1H, t, J = 5.8 Hz),4.34(1H, t, J = 5.8 Hz), 6.94(1H, s) mp: 182(decomp.) 222 2 ESI+: 283NMR-A: 1.76-1.88(2H, m), 2.38(3H, s), 2.61-2.68(2H, m), 2.73(2H, t, J =6.4 Hz), 2.95- 3.22(8H, m), 6.44(1H, d, J = 2.9 Hz), 6.60-6.65(2H, m),7.02(1H, s), 7.78-7.84(1H, m) mp: 180(decomp.) 223 2 ESI+: 353, 355 NMR:1.12(3H, d, J = 6.3 Hz), 1.60-1.68(1H, m), 1.76-1.86(1H, m),2.66-2.70(2H, m), 2.81(1H, dd, J = 14.1, 3.4 Hz), 2.86-2.96(7H, m),3.22-3.25(2H, m), 3.27(3H, s), 3.36-3.41 (2H, m), 3.81-3.89(1H, m),6.41(2H, s), 6.82(1H, s) mp: 161(decomp.) 224 2 ESI+: 315 NMR:0.28-0.35(1H, m), 0.38-0.44(1H, m), 0.95-1.00(5H, m), 1.55-1.62(1H, m),1.65- 1.76(2H, m), 2.57-2.60(2H, m), 2.83-2.85(2H, m), 2.99-3.13(8H, m),3.17(3H, s), 3.19- 3.23(2H, m), 3.52-3.59(1H, m), 6.41(2H, s), 6.63(1H,s) 225 2 ESI+: 261 NMR: 1.00(3H, t, J = 7.2 Hz), 1.33-1.47(2H, m),2.62-2.73(2H, m), 2.81(3H, s), 2.94-3.15 (8H, m), 3.16-3.31(2H, br),4.21-4.35(2H, br), 6.64(1H, s), 9.42(2H, s) mp: 151-152 226 2 ESI+: 247NMR: 1.09(3H, t, J = 7.4 Hz), 2.70-2.95(5H, m), 2.97-3.17(8H, m),3.18-3.39(2H, br), 4.23- 4.39(2H, m), 6.67(1H, s), 9.48(2H, s) mp:184-185

TABLE 170 Ex Syn Dat 227 2 ESI+: 329 NMR: 0.30-0.40(1H, m),0.54-0.64(1H, m), 0.96-1.06(2H, m), 1.33-1.45(1H, m), 1.58- 1.67(1H, m),1.70-1.85(2H, m), 1.92-2.01(1H, m), 2.85-3.37(11H, m), 3.46-3.55(1H, m),3.61-3.69(1H, m), 3.72-3.80(1H, m), 3.95-4.03(1H, m), 4.05-4.18(2H, m),6.53(1H, s), 9.19-9.37(2H, br) mp: 156-158 228 2 ESI+: 305 NMR:0.32-0.41(1H, m), 0.48-0.55(1H, m), 0.95-1.04(2H, m), 1.27(3H, dd, J =23.9, 6.3 Hz), 1.56-1.65(1H, m), 2.72-3.01(6H, m), 3.04-3.31(6H, m),3.97-4.09(2H_(:), m), 4.97- 5.01(1H, m), 6.38(1H, s), 6.48(1H, s) mp:117(decomp.) 229 2 ESI+: 331 NMR: 0.41-0.48(2H, m), 0.97-1.04(2H, m),1.07(6H, d, J = 6.1 Hz), 1.58-1.66(1H, m), 2.85-2.92(2H, m),2.99-3.18(8H, m), 3.18-3.27(2H, m), 3.47-3.57(1H, m), 3.63(2H, t, J =5.9 Hz), 3.99-4.05(2H, m), 6.43(2H, s), 6.51(1H, s) mp: 117(decomp.) 2302 ESI+: 331 NMR: 0.37-0.44(2H, m), 0.96-1.03(2H, m), 1.11(6H, s),1.63-1.72(1H, m), 2.87-2.94(2H, m), 3.04-3.16(9H, m), 3.21-3.33(4H, m),4.10-4.17(2H, m), 6.51(1H, s), 8.99-9.17(2H, br) mp: 155-156 231 2 ESI+:345 NMR: 0.33-0.41(2H, m), 0.90(6H, s), 0.96-1.03(2H, m), 1.65-1.74(1H,m), 2.88-2.95(2H, m), 3.00(2H, s), 3.03-3.17(9H, m), 3.22-3.30(4H, m),4.09-4.16(2H, m), 6.50(1H, s), 9.22-9.35(2H, br) mp: 141-145 232 2 ESI+:371 NMR: 0.39-0.46(2H, m), 0.97-1.04(2H, m), 1.57-1.66(1H, m),2.76-2.82(2H, m), 2.84- 2.97(4H, m), 3.07-3.19(6H, m), 3.88(2H, t, J =6.0 Hz), 3.99-4.12(4H, m), 6.37(1H, s), 6.48(1H, s) mp: 187(decomp.) 2332 ESI+: 345 NMR: 0.29-0.38(1H, m), 0.51-0.60(1H, m), 0.93-1.05(2H, m),1.57-1.66(1H, m), 2.72- 3.25(12H, m), 3.32-3.47(2H, m), 3.55-3.74(4H,m), 3.85-3.93(1H, m), 3.95-4.08(2H, m), 6.38(1H, s), 6.47(1H, s) mp:204(decomp.) 234 2 ESI+: 233 NMR: 0.96(3H, t, J = 7.6 Hz), 1.48-1.66(2H,m), 2.76-2.86(4H, m), 2.89(1H, dd, J = 11.8, 7.7 Hz), 2.94-3.09(4H, m),3.27(1H, dd, J = 11.8, 2.4 Hz), 3.77-3.86(1H, m), 5.32-5.87(1H, br),6.37(1H, s), 6.43(2H, s), 6.48(1H, s) mp: 193(decomp.)

TABLE 171 Ex Syn Dat 235 2 ESI+: 249 NMR: 2.76-2.87(4H, m),2.94-3.07(5H, m), 3.25(1H, dd, J = 11.9, 2.6 Hz), 3.30(3H, s),3.41-3.52(2H, m), 4.07-4.14(1H, m), 5.40-5.83(1H, br), 6.38(1H, s),6.43(2H, s), 6.50(1H, s) 236 2 ESI+: 247 NMR: 0.87-0.97(3H, m),1.32-1.63(4H, m), 2.75-2.86(4H, m), 2.90(1H, dd, J = 11.8, 7.7 Hz),2.94-3.09(4H, m), 3.26(1H, dd, J = 11.8, 2.4 Hz), 3.86-3.94(1H, m),5.31-5.86(1H, br), 6.36(1H, s), 6.43(2H, s), 6.47(1H, s) mp:191(decomp.) 237 2 ESI+: 347 NMR: 0.33-0.41(1H, m), 0.46-0.54(1H, m),0.97-1.08(2H, m), 1.54-1.62(1H, m), 2.84- 2.98(3H, m), 2.98-3.12(5H, m),3.14-3.25(6H, m), 3.27-3.41(6H, m), 3.61-3.70(1H, m), 3.96-4.08(2H, m),6.43(2H, s), 6.51(1H, s) mp: 150-154 238 2 ESI+: 291 NMR: 0.96(3H, t, J= 7.5 Hz), 1.48-1.64(2H, m), 2.79-2.93(4H, m), 2.97-3.10(5H, m),3.25(3H, s), 3.27-3.39(2H, m), 3.40-3.55(3H, m), 3.80-3.89(1H, m),6.44(2H, s), 6.52(1H, s), 6.53(1H, s) mp: 147(decomp.) 239 2 ESI+: 305NMR: 0.88-0.96(3H, m), 1.34-1.60(4H, m), 2.79-2.93(4H, m), 2.95-3.10(5H,m), 3.25 (3H, s), 3.29-3.38(2H, m), 3.39-3.55(3H, m), 3.89-3.97(1H, m),6.44(2H, s), 6.51(1H, s), 6.53(1H, s) mp: 151(decomp.) 240 2 ESI+: 247NMR: 0.97(3H, t, J = 7.5 Hz), 1.50-1.67(2H, m), 2.78(3H, s),2.80-2.92(5H, m), 2.97-3.07 (4H, m), 3.22(1H, dd, J = 11.6, 2.4 Hz),3.97-4.05(1H, m), 6.43(2H, s), 6.51(1H, s), 6.53(1H, s) mp: 166(decomp.)241 2 ESI+: 261 NMR: 0.88-0.97(3H, m), 1.33-1.63(4H, m), 2.78(3H, s),2.80-2.93(5H, m), 2.96-3.09(4H, m), 3.21(1H, dd, J = 11.6, 2.3 Hz),4.04-4.14(1H, m), 6.44(2H, s), 6.50(1H, s), 6.53(1H, s) mp: 152-153 2422 ESI+: 347 NMR: 0.31-0.42(1H, m), 0.44-0.57(1H, m), 0.95-1.11(2H, m),1.53-1.64(1H, m), 2.80- 2.97(3H, m), 2.98-3.13(5H, m), 3.13-3.26(6H, m),3.27-3.42(6H, m), 3.62-3.70(1H, m), 3.96-4.09(2H, m), 6.43(2H, s),6.51(1H, s) mp: 156-158

TABLE 172 Ex Syn Dat 243 2 ESI+: 317 NMR: 0.30-0.42(1H, m),0.46-0.59(1H, m), 0.95-1.09(5H, m), 1.55-1.67(1H, m), 2.80- 3.30(14H,m), 3.33-3.43(1H, m), 3.62-3.75(1H, m), 3.95-4.09(2H, m), 6.42(2H, s),6.50 (1H, s) mp: 133-136 244 2 ESI+: 247 NMR: 1.17(3H, t, J = 7.3 Hz),2.16(3H, s), 2.66(2H, q, J = 7.3 Hz), 2.87-3.09(10H, m), 3.98- 4.04(2H,m), 6.44(2H, s), 6.50(1H, s) mp: 200(decomp.) 245 2 ESI+: 291 NMR:1.82-1.92(2H, m), 2.15(3H, s), 2.63-2.71(2H, m), 2.79-3.03(10H, m),3.23(3H, s), 3.40(2H, t, J = 5.2 Hz), 3.99-4.06(2H, m), 6.37(1H, s),6.46(1H, s) mp: 160-163 246 2 ESI+: 291 NMR: 1.13(3H, t, J = 6.9 Hz),2.19(3H, s), 2.83(2H, t, J = 6.2 Hz), 2.87-3.12(10H, m), 3.48 (2H, q, J= 6.9 Hz), 3.65(2H, t, J = 6.2 Hz), 3.99-4.09(2H, m), 6.44(2H, s),6.50(1H, s) mp: 152-155 247 2 ESI+: 279 NMR: 1.94-2.11 (2H, m), 2.16(3H,s), 2.69-2.79(2H, m), 2.88-3.10(10H, m), 4.01-4.08 (2H, m), 4.55(2H, dt,J = 48.1, 6.9 Hz), 6.44(2H, s), 6.51(1H, s) mp: 187-190 248 2 ESI+: 327NMR: 0.28-0.32(1H, m), 0.44-0.48(1H, m), 0.97-0.99(2H, m), 1.30-1.39(1H,m), 1.56- 1.79(5H, m), 1.87-1.94(1H, m), 2.58-2.61(2H, m), 2.85-2.86(2H,m), 2.99-3.08(6H, m), 3.17-3.47(4H, m), 3.58-3.64(1H, m), 3.70-3.76(1H,m), 4.02-4.09(1H, m), 6.42(2H, s), 6.64(1H, s) 249 2 ESI+: 327 NMR:0.28-0.32(1H, m), 0.44-0.48(1H, m), 0.97-0.99(2H, m), 1.30-1.39(1H, m),1.56- 1.79(5H, m), 1.87-1.94(1H, m), 2.58-2.61(2H, m), 2.85-2.87(2H, m),2.99-3.08(6H, m), 3.17-3.47(4H, m), 3.58-3.64(1H, m), 3.70-3.76(1H, m),4.02-4.09(1H, m), 6.42(2H, s), 6.64(1H, s) 250 2 ESI+: 343 NMR:0.36-0.50(2H, m), 0.97-1.06(2H, m), 1.13-1.29(2H, m), 1.56-1.74(3H, m),1.90- 2.06(1H, m), 2.84(2H, d, J = 7.3 Hz), 2.89-2.98(2H, m),3.03-3.18(6H, m), 3.23-3.35(4H, m), 3.79-3.87(2H, m), 4.00-4.08(2H, m),6.53(1H, s), 9.13-9.41(2H, br) mp: 153-155

TABLE 173 Ex Syn Dat 251 2 ESI+: 343 NMR: 0.28-0.40(1H, m),0.50-0.62(1H, m), 0.94-1.03(2H, m), 1.10-1.25(1H, m), 1.33- 1.62(5H, m),1.71-1.80(1H, m), 2.24(2H, s), 2.70-3.10(10H, m), 3.10-3.21(1H, m),3.30-3.48(2H, m), 3.63-3.70(1H, m), 3.82-3.89(1H, m), 3.93-4.07(2H, m),6.46(1H, s) mp: 171(decomp.) 252 2 ESI+: 303 NMR: 1.43-1.54(1H, m),1.73-1.90(2H, m), 2.00-2.06(1H, m), 2.25(3H, s), 2.83-3.23(11H, m),3.35-3.45(1H, m), 3.66-3.84(2H, m), 4.10-4.30(3H, m), 6.57(1H, s),9.57(2H, br) 253 2 ESI+: 303 NMR: 1.41-1.53(1H, m), 1.70-1.88(2H, m),1.94-2.05(1H, m), 2.23(3H, s), 1.77-2.85(2H, m), 2.93-3.16(9H, m),3.31-3.42(1H, m), 3.65-3.89(2H, m), 4.06-4.25(3H, m), 6.54(1H, s),9.40(2H, s) 254 2 ESI+: 331 NMR: 0.34-0.49(2H, m), 0.92(3H, d, J = 6.7Hz), 0.96-1.03(2H, m), 1.57-1.69(1H, m), 2.08- 2.23(1H, m), 2.80(1H, dd,J = 13.4, 7.8 Hz), 2.86-2.99(3H, m), 3.02-3.14(6H, m), 3.14- 3.21(4H,m), 3.21-3.26(2H, m), 3.30(1H, dd, J = 9.2, 5.0 Hz), 3.95-4.08(2H, m),6.48(3H, s), 6.52(1H, s) 255 2 ESI+: 329 NMR: 0.37-0.50(2H, m),0.93-1.05(2H, m), 1.50-1.68(2H, m), 1.92-2.04(1H, m), 2.53- 2.65(1H, m),2.76-2.85(2H, m), 2.86-3.22(10H, m), 3.37-3.47(1H, m), 3.57-3.79(3H, m),3.97-4.09(2H, m), 6.37(1H, s), 6.48(1H, s) mp: 117-118 256 2 ESI+: 279NMR: 1.31(3H, dd, J = 5.87, 24.2 Hz), 2.19(3H, s), 2.70-3.17(12H, m),4.03-4.12(2H, m), 4.96-5.19(1H, m), 6.44(2H, s), 6.51(1H, s) mp: 165-168257 2 ESI+: 335 NMR: 0.46-0.62(2H, m), 0.89-1.01(2H, m), 1.64-1.76(1H,m), 2.25(2H, s), 2.75-2.85(2H, m), 2.88-3.02(6H, m), 3.11-3.22(2H, m),3.86-3.98(2H, m), 4.19(2H, s), 6.54(1H, s), 7.24-7.31(1H, m),7.33-7.40(2H, m), 7.42-7.49(2H, m) mp: 107-110 258 2 ESI+: 369, 371 NMR:0.47-0.62(2H, m), 0.87-1.00(2H, m), 1.65-1.78(1H, m), 2.28(4H, s),2.82-2.92(2H, m), 2.94-3.13(6H, m), 3.17-3.29(2H, m), 3.90-4.01(2H, m),4.20(2H, s), 6.58(1H, s), 7.32-7.45(3H, m), 7.50-7.54(1H, m) mp: 139-141

TABLE 174 Ex Syn Dat 259 2 ESI+: 369, 371 0.41-0.56(2H, m),0.72-0.85(2H, m), 1.52-1.63(1H, m), 2.28(4H, s), 2.81-2.93(2H, m),2.98-3.12(6H, m), 3.16-3.27(2H, m), 3.94-4.04(2H, m), 4.23(2H, s),6.60(1H, s), 7.33(1H, dt, J = 1.61, 7.48 Hz), 7.40-7.49(2H, m),7.80-7.88(1H, m) mp: 106-109 260 2 ESI+: 353 0.47-0.63(2H, m),0.83-1.00(2H, m), 1.60-1.74(1H, m), 2.25(4H, s), 2.76-2.85(2H, m),2.88-3.05(6H, m), 3.11-3.26(2H, m), 3.87-3.99(2H, m), 4.21(2H, s),6.55(1H, s), 7.07- 7.14(1H, m), 7.24-7.32(2H, m), 7.38-7.45(1H, m) mp:102-105 261 2 ESI+: 301 NMR: 1.85-2.01(1H, m), 2.80(3H, s),2.94-3.26(11H, m), 3.74-3.92(2H, m), 4.10-4.31 (4H, m), 5.66(1H, s),6.69(1H, s), 9.38-9.62(2H, br) 262 2 ESI+: 301 NMR: 0.37-0.51(2H, m),0.91(6H, d, J = 6.6 Hz), 0.96-1.04(2H, m), 1.58-1.71(1H, m),1.92-2.08(1H, m), 2.72-2.83(2H, m), 2.89-2.99(2H, m), 3.03-3.19(6H, m),3.23-3.34(2H, m), 3.99-4.07(2H, m), 6.53(1H, s), 9.24-9.42(2H, br) mp:160-162 263 2 ESI+: 343 NMR: 0.30-0.49(2H, m), 0.90-1.05(2H, m),1.12-1.27(1H, m), 1.41-1.67(3H, m), 1.73- 1.85(1H, m), 1.91-2.05(1H, m),2.66-2.99(8H, m), 3.00-3.21(5H, m), 3.22-3.32(1H, m), 3.71-3.78(1H, m),3.82-3.90(1H, m), 3.96-4.08(2H, m), 6.37(1H, s), 6.47(1H, s) mp: 186-189264 2 ESI+: 293 NMR: 1.07(3H, t, J = 7.3 Hz), 1.95-2.15(2H, m), 2.68(2H,q, J = 7.3 Hz), 2.80-2.92(2H, m), 2.93-3.18(10H, m), 4.07-4.19(2H, m),4.56(2H, dt, J = 47.4, 5.7 Hz), 6.55(1H, s), 9.24- 9.52(2H, br) mp:153-154 265 2 ESI+: 353 NMR: 0.46-0.57(2H, m), 0.84-0.96(2H, m),1.64-1.74(1H, m), 2.80-3.07(8H, m), 3.14- 3.25(2H, m), 3.88-3.97(2H, m),4.24(2H, s), 6.38(1H, s), 6.54(1H, s), 7.13-7.28(2H, m), 7.30-7.39(1H,m), 7.66(1H, dt, J = 1.66, 7.68 Hz) mp: 133-136 266 2 ESI+: 331 NMR:0.37-0.52(2H, m), 0.95-1.06(2H, m), 1.43-1.55(2H, m), 1.58-1.74(3H, m),2.82- 2.95(4H, m), 2.98-3.12(6H, m), 3.16-3.27(5H, m), 3.33(2H, t, J =6.4 Hz), 3.94-4.02(2H, m), 6.43(2H, s), 6.51(1H, s)

TABLE 175 Ex Syn Dat 267 2 ESI+: 393 NMR: 0.28-0.43(1H, m),0.44-0.58(1H, m), 0.94-1.10(2H, m), 1.52-1.64(1H, m), 2.81- 3.09(6H, m),3.09-3.25(3H, m), 3.25-3.34(2H, m), 3.34-3.46(1H, m), 3.94-4.17(3H, m),4.29(1H, dd, J = 11.5, 2.4 Hz), 4.53-4.63(1H, m), 6.42(1.5H, s),6.52(1H, s), 6.69- 6.76(1H, m), 6.77-6.87(3H, m) mp: 179-182 268 2 ESI+:365 NMR: 0.40-0.52(2H, m), 0.98-1.10(2H, m), 1.61-1.71(1H, m),2.85-2.93(2H, m), 2.98- 3.12(4H, m), 3.17-3.29(4H, m), 3.33-3.41(2H, m),4.02-4.10(2H, m), 4.25(2H, t, J = 5.9 Hz), 6.44(2H, s), 6.53(1H, s),6.90-6.97(3H, m), 7.24-7.32(2H, m) 269 2 ESI+: 305 NMR: 1.04(3H, t, J =7.4 Hz), 1.14(3H, t, J = 7.0 Hz), 2.71(2H, q, J = 7.4 Hz), 2.76-2.95(10H, m), 2.98-3.07(2H, m), 3.49(2H, q, J = 7.0 Hz), 3.64(2H, t, J =5.9 Hz), 4.04- 4.11(2H, m), 6.38(1H, s), 6.45(1H, s) mp: 179-181 270 2ESI+: 379 NMR: 0.46-0.57(2H, m), 0.84-0.97(2H, m), 1.25(3H, t, J = 7.09Hz), 1.60-1.72(1H, m), 2.87-2.95(2H, m), 2.97-3.15(6H, m), 3.20-3.33(2H,m), 3.85-3.93(2H, m), 3.97(2H, q, J = 7.09 Hz), 4.16(2H, s), 6.45(2H,s), 6.56(1H, s), 6.93-6.00(2H, m), 7.24(1H, dt, J = 1.42, 7.34 Hz),7.55(1H, dd, J = 1.42.8.22 Hz) mp: 215(decomp.) 271 2 ESI+: 309 NMR:0.38-0.49(2H, m), 1.01-1.15(2H, m), 1.62-1.75(1H, m), 2.87-2.94(2H, m),2.99- 3.10(4H, m), 3.11-3.17(2H, m), 3.20-3.27(2H, m), 3.35(2H, dt, J =4.3, 15.2 Hz), 4.04- 4.12(2H, m), 6.22-6.40(1H, m), 6.44(2H, s),6.55(1H, s) mp: 198-201 272 2 ESI+: 415 NMR: 0.48-0.59(2H, m),0.88-0.98(2H, m), 1.69-1.80(1H, m), 2.89-2.97(2H, m), 3.01- 3.17(6H, m),3.23-3.32(2H, m), 3.91-4.00(2H, m), 4.30(2H, s), 6.48(2H, s), 6.58(1H,s), 7.22-7.27(1H, m), 7.30-7.35(1H, m), 7.38-7.42(1H, m) mp:200(decomp.) 273 2 ESI+: 415 NMR: 0.48-0.64(2H, m), 0.91-1.01(2H, m),1.64-1.80(1H, m), 2.86-3.17(8H, m), 3.21- 3.33(2H, m), 3.88-3.99(2H, m),4.21(2H, s), 6.45(2H, s), 6.59(1H, s), 7.28(1H, dd, J = 1.22, 8.36 Hz),7.41(1H, d, J = 8.36 Hz), 7.46(1H, d, J = 1.22 Hz) mp: 161-164 274 2ESI+: 377 NMR: 0.46-0.64(2H, m), 0.93-1.10(2H, m), 1.67-1.81(1H, m),2.87-3.00(4H, m), 3.01- 3.35(8H, m), 3.88-3.99(2H, m), 4.09(2H, s),4.46-4.59(2H, m), 6.45(2H, s), 6.57(1H, s), 6.73(1H, d, J = 8: 17 Hz),7.11-7.16(1H, m), 7.29(1H, s) mp: 215(decomp.)

TABLE 176 Ex Syn Dat 275 2 ESI+: 393 NMR: 0.40-0.63(2H, m),0.78-1.00(2H, m), 1.56-1.77(1H, m), 2.83-2.96(2H, m), 2.99- 3.17(6H, m),3.20-3.34(2H, m), 3.84-3.93(2H, m), 4.14(2H, s), 4.17-4.25(4H, m), 6.44(2H, s), 6.56(1H, s), 6.76(1H, dd, J = 1.37, 8.27 Hz), 6.84(1H, t, J =8.27 Hz), 7.10(1H, dd, J = 1.37, 8.27 Hz) mp: 184-187 276 2 ESI+: 349NMR: 0.45-0.58(2H, m), 0.75-0.88(2H, m), 1.55-1.66(1H, m), 2.17(3H, s),2.84-2.96(2H, m), 2.99-3.14(6H, m), 3.19-3.29(2H, m), 3.93-4.01(2H, m),4.14(2H, s), 6.42(2H, s), 6.59(1H, s), 7.14-7.17(2H, m), 7.21-7.28(1H,m), 7.68-7.75(1H, m) mp: 163-166 277 2 ESI+: 349 NMR: 0.50-0.63(2H, m),0.92-1.03(2H, m), 1.67-1.78(1H, m), 2.31(3H, s), 2.88-2.99(4H, m),3.03-3.15(4H, m), 3.24-3.33(2H, m), 3.91-3.99(2H, m), 4.16(2H, s),6.45(2H, s), 6.58(1H, s), 7.05-7.11(1H, m), 7.22-7.29(3H, m) mp: 192-195278 4 ESI+: 245 NMR: 1.20(6H, s), 2.31(2H, s), 2.95-3.18(8H, m),6.69(1H, s), 7.12(1H, s), 9.24-9.38(1.8H, br), 10.12(1H, s) mp: 270-272279 4 ESI+: 231 NMR: 1.32(6H, s), 1.78-1.89(2H, m), 2.72-2.81(2H, m),3.00-3.21(8H, m), 6.90-7.16(2H, m), 9.29-9.48(2H, br) mp: 270-273 280282 ESI+: 353, 355 NMR: 1.27(3H, d, J = 7.2 Hz), 1.69-1.79(2H, m),2.61-2.77(4H, m), 2.93-3.46(9H, m), 3.28(3H, s), 3.72(2H, t, J = 6.5Hz), 6.47(2H, s), 6.85(1H, s) mp: 188(decomp.) 281 282 ESI+: 315 NMR:0.32-0.43(2H, m), 0.97-1.01(2H, m), 1.27(3H, d, J = 7.2 Hz),1.59-1.77(3H, m), 2.62- 2.70(2H, m), 2.77-2.84(1H, br), 3.03-3.28(8H,m), 3.23(3H, s), 3.43-3.58(2H, m), 3.56(2H, t, J = 6.3 Hz), 6.43(2H, s),6.67(1H, s) mp: 195(decomp.) 282 282 ESI+: 353, 355 NMR: 1.24(3H, d, J =7.4 Hz), 1.69-1.76(2H, m), 2.62-2.75(4H, m), 2.90-3.31(8H, m), 3.28(3H,s), 3.72(2H, t, J = 6.5 Hz), 3.84-3.89(1H, m), 6.49(2H, s), 6.79(1H, s)mp: 184(decomp.) 283 2 ESI+: 371 NMR: 0.46-0.60(2H, m), 0.81-0.95(2H,m), 1.61-1.75(1H, m), 2.78-2.89(2H, m), 2.91- 3.01(4H, m), 3.01-3.08(2H,m), 3.14-3.25(2H, m), 3.91-3.99(2H, m), 4.22(2H, s), 6.40 (1H, s),6.55(1H, s), 7.12-7.30(2H, m), 7.41-7.52(1H, m) mp: 195(decomp.)

TABLE 177 Ex Syn Dat 284 2 ESI+: 371 NMR: 0.46-0.55(2H, m),0.84-0.94(2H, m), 1.64-1.75(1H, m), 2.81-3.09(8H, m), 3.14- 3.25(2H, m),3.88-3.99(2H, m), 4.28(2H, s), 6.38(1H, s), 6.55(1H, s), 7.20-7.29(1H,m), 7.30-7.40(1H, m), 7.44-7.52(1H, m) mp: 157-159 285 2 ESI+: 387, 389NMR: 0.41-0.56(2H, m), 0.79-0.93(2H, m), 1.61-1.75(1H, m), 2.78-3.09(8H,m), 3.15- 3.24(2H, m), 3.92-3.98(2H, m), 4.27(2H, s), 6.39(1H, s),6.55(1H, s), 7.25-7.32(1H, m), 7.47-7.55(1H, m), 7.62-7.70(1H, m) mp:181-184 286 2 ESI+: 377 NMR: 0.44-0.62(2H, m), 0.85-1.02(2H, m),1.62-1.79(1H, m), 2.83-3.38(12H, m), 3.83- 3.99(2H, m), 4.10(2H, s),4.49(2H, t, J = 8.51 Hz), 6.47(2H, s), 6.57(1H, s), 6.81- 6.90(1H, m),7.14(1H, d, J = 6.8 Hz), 7.30(1H, d, J = 8.1 Hz) mp: 190(decomp.) 287 2ESI+: 335 NMR: 0.29-0.43(1H, m), 0.43-0.57(1H, m), 0.92-1.10(2H, m),1.56-1.68(1H, m), 2.82- 2.92(2H, m), 2.95-3.39(13H, m), 3.69-3.86(1H,m), 3.96-4.11(2H, m), 4.32-4.65(2H, m), 6.43(2H, s), 6.52(1H, s) 288 2ESI+: 379 NMR: 0.54-0.62(2H, m), 0.94-1.04(2H, m), 1.68-1.79(1H, m),2.90-3.17(8H, m), 3.24- 3.34(5H, m), 3.90-3.98(2H, m), 4.20(2H, s),4.41(2H, s), 6.44(2H, s), 6.58(1H, s), 7.15-7.24(1H, m), 7.29-7.42(3H,m) mp: 190-193 289 2 ESI+: 371 NMR: 0.44-0.56(2H, m), 0.85-0.96(2H, m),1.65-1.75(1H, m), 2.80-3.08(8H, m), 3.14- 3.26(2H, m), 3.88-3.98(2H, m),4.20(2H, s), 6.38(1H, s), 6.54(1H, s), 7.13(1H, dt, J = 2.5, 8.5 Hz),7.18-7.26(1H, m), 7.64-7.72(1H, m) mp: 220(decomp.) 290 2 ESI+: 387, 389NMR: 0.44-0.58(2H, m), 0.82-0.96(2H, m), 1.64-1.75(1H, m), 2.89-2.97(2H,m), 3.00- 3.16(6H, m), 3.21-3.32(2H, m), 3.90-4.01(2H, m), 4.22(2H, s),6.45(2H, s), 6.58(1H, s), 7.22-7.29(1H, m), 7.38-7.44(1H, m), 7.69(1H,dd, J = 6.7, 3.0 Hz) mp: 165-168 291 2 ESI+: 393 NMR: 0.47-0.60(2H, m),0.92-1.02(2H, m), 1.65-1.76(1H, m), 2.81-3.04(8H, m), 3.17- 3.27(2H, m),3.86-3.95(2H, m), 4.06(2H, s), 4.22(4H, s), 6.38(1H, s), 6.54(1H, s),6.79-6.89(2H, m), 6.91-6.95(1H, m) mp: 165-168

TABLE 178 Ex Syn Dat 292 2 ESI+: 317 NMR: 0.14-0.25(1H, m),0.58-0.68(1H, m), 0.91(3H, d, J = 6.9 Hz), 0.97-1.09(2H, m), 1.55-1.68(1H, m), 2.75-3.19(8H, m), 3.25(3H, s), 3.28-3.48(3H, m), 3.61(2H,t, J = 6.1 Hz), 3.86(1H, dd, J = 10.5, 1.6 Hz), 3.92(1H, dd, J = 10.6,2.3 Hz), 6.43(2H, s), 6.52(1H, s) mp: 183(decomp.) 293 2 ESI+: 379 NMR:0.43-0.55(2H, m), 0.76-0.87(2H, m), 1.53-1.65(1H, m), 2.86-3.12(8H, m),3.18- 3.29(5H, m), 3.88-3.97(2H, m), 4.23(2H, s), 4.36(2H, s), 6.44(2H,s), 6.60(1H, s), 7.20- 7.29(1H, m), 7.31-7.43(2H, m), 7.82(1H, d, J =7.8 Hz) mp: 180(decomp.) 294 2 ESI+: 335 NMR: 0.31-0.43(1H, m),0.44-0.54(1H, m), 0.94-1.10(2H, m), 1.55-1.67(1H, m), 2.82- 2.93(2H, m),2.95-3.40(13H, m), 3.68-3.86(1H, m), 3.97-4.12(2H, m), 4.33-4.65(2H, m),6.43(2H, s), 6.52(1H, s) 295 2 ESI+: 367 NMR: 0.43-0.46(2H, m),1.00-1.06(2H, m), 1.60-1.67(1H, m), 2.82-2.85(2H, m), 2.98- 3.03(4H, m),3.15-3.17(2H, m), 3.20-3.23(2H, m), 3.38-3.41(2H, m), 4.05-4.07(2H, m),4.60(2H, t, J = 6.1 Hz), 6.42(2H, s), 6.51(1H, s), 8.20(2H, s), 8.22(1H,s) mp: 170(decomp.) 296 2 ESI+: 438 NMR: 0.44-0.48(2H, m), 1.05-1.10(2H,m), 1.63-1.70(1H, m), 2.84-2.86(2H, m), 2.98- 3.04(4H, m), 3.18-3.23(4H,m), 3.41-3.44(2H, m), 3.94(3H, s), 4.06-4.09(2H, m), 4.46- 4.49(2H, m),6.42(2H, s), 6.52(1H, s), 6.99(1H, d, J = 7.1 Hz), 7.71(1H, d, J = 10.9Hz) mp: 125-128 297 2 ESI+: 426 NMR: 0.42-0.46(2H, m), 0.97-1.02(2H, m),1.57-1.64(1H, m), 2.83-2.85(2H, m), 2.98- 3.03(4H, m), 3.16-3.21(4H, m),3.34-3.37(2H, m), 4.05-4.07(2H, m), 4.56-4.59(2H, m), 6.41(2H, s),6.52(1H, s), 7.82-7.90(2H, m) mp: 178(decomp.) 298 2 ESI+: 365 NMR:0.42-0.56(2H, m), 0.78-0.91(2H, m), 1.57-1.68(1H, m), 2.83-3.14(8H, m),3.21- 3.33(2H, m), 3.72(3H, s), 3.85-3.96(2H, m), 4.15(2H, s), 6.45(2H,s), 6.57(1H, s), 6.93-7.04(2H, m), 7.22-7.30(1H, m), 7.53-7.61(1H, m)mp: 195(decomp.) 299 2 ESI+: 365 NMR: 0.51-0.64(2H, m), 0.93-1.03(2H,m), 1.68-1.78(1H, m), 2.84-3.15(8H, m), 3.22- 3.33(2H, m), 3.74(3H, s),3.86-3.97(2H, m), 4.18(2H, s), 6.44(2H, s), 6.57(1H, s), 6.81-6.88(1H,m), 6.96-7.04(2H, m), 7.24-7.31(1H, m) mp: 220(decomp.)

TABLE 179 Ex Syn Dat 300 2 ESI+: 419 NMR: 0.44-0.58(2H, m),0.78-0.91(2H, m), 1.55-1.67(1H, m), 2.87-3.15(8H, m), 3.21- 3.33(2H, m),3.87-3.98(2H, m), 4.27(2H, s), 6.45(2H, s), 6.66(1H, s), 7.33-7.39(1H,m), 7.41-7.52(2H, m), 7.84-7.91(1H, m) mp: 210(decomp.) 301 2 ESI+: 379NMR: 0.45-0.56(2H, m), 0.82-0.95(2H, m), 1.58-1.69(1H, m), 2.27(3H, s),2.86-3.15(8H, m), 3.22-3.32(2H, m), 3.68(3H, s), 3.78-3.96(2H, m),4.10(2H, s), 6.45(2H, s), 6.56(1H, s), 6.86(1H, d, J = 8.3 Hz), 7.05(1H,dd, J = 1.8, 8.3 Hz), 7.38(1H, d, J = 1.8 Hz) mp: 205(decomp.) 302 2ESI+: 383 NMR: 0.44-0.60(2H, m), 0.76-0.89(2H, m), 1.55-1.66(1H, m),2.89-2.96(2H, m), 3.00- 3.12(6H, m), 3.21-3.30(2H, m), 3.72(3H, s),3.91-3.97(2H, m), 4.11(2H, s), 6.45(2H, s), 6.58(1H, s), 6.95-7.01(1H,m), 7.04-7.11(1H, m), 7.35-7.42(1H, m) mp: 189-192 303 2 ESI+: 399, 401NMR: 0.39-0.57(2H, m), 0.74-0.89(2H, m), 1.53-1.68(1H, m), 2.81-3.15(8H,m), 3.20- 3.32(2H, m), 3.73(3H, s), 3.88-3.99(2H, m), 4.10(2H, s),6.45(2H, s), 6.58(1H, s), 7.01(1H, d, J = 8.7 Hz), 7.31(1H, dd, J = 2.6,8.7 Hz), 7.59(1H, d, J = 2.59 Hz) mp: 193-196 304 2 ESI+: 427 NMR:0.34-0.50(2H, m), 0.97-1.07(2H, m), 1.60-1.67(1H, m), 2.82-2.85(2H, m),2.96- 3.05(4H, m), 3.09-3.46(6H, m), 3.22(3H, s), 3.46-3.53(2H, m),4.03-4.05(2H, m), 4.83- 4.86(1H, m), 6.42(2H, s), 6.47(1H, s),6.92-6.97(1H, m), 7.08-7.22(3H, m) mp: 132-133 305 2 ESI+: 427 NMR:0.34-0.49(2H, m), 0.99-1.11(2H, m), 1.61-1.68(1H, m), 2.82-2.86(2H, m),2.89- 3.43(10H, m), 3.22(3H, s), 3.44-3.52(2H, m), 3.97-4.06(2H, m),4.81-4.87(1H, m), 6.42 (2H, s), 6.45(1H, s), 6.73-6.78(3H, m),7.25-7.31(1H, m) mp: 174(decomp.) 306 2 ESI+: 427 NMR: 0.35-0.51(2H, m),0.97-1.09(2H, m), 1.60-1.67(1H, m), 2.80-3.51(14H, m), 3.21 (3H, s),3.97-4.06(2H, m), 4.71-4.76(1H, m), 6.43(2H, s), 6.47(1H, s),6.91-6.95(2H, m), 7.07-7.11(2H, m) mp: 138-140 307 2 ESI+: 445 NMR:0.35-0.50(2H, m), 0.97-1.08(2H, m), 1.59-1.66(1H, m), 2.79-2.86(2H, m),2.89- 3.43(10H, m), 3.21(3H, s), 3.44-3.52(2H, m), 4.03-4.05(2H, m),4.75-4.80(1H, m), 6.43 (2H, s), 6.47(1H, s), 6.95-7.00(1H, m), 7.17(1H,td, J = 9.3, 5.6 Hz), 7.26(1H, ddd, J = 11.5, 8.7, 2.9 Hz) mp: 150-151

TABLE 180 Ex Syn Dat 308 2 ESI+: 463 NMR: 0.35-0.46(2H, m),0.97-1.12(2H, m), 1.61-1.68(1H, m), 2.78-3.58(14H, m), 3.21 (3H, s),3.96-4.05(2H, m), 4.77-4.82(1H, m), 6.43(3H, s), 6.84-6.88(2H, m) mp:155(decomp.) 309 2 ESI+: 461, 463 NMR: 0.34-0.39(1H, m), 0.46-0.51(1H,m), 0.98-1.10(2H, m), 1.61-1.68(1H, m), 2.80- 3.42(12H, m), 3.21(3H, s),3.45-3.53(2H, m), 4.02-4.07(2H, m), 4.83-4.88(1H, m), 6.43 (2H, s),6.48(1H, s), 7.12-7.21(2H, m), 7.41(1H, dd, J = 8.3, 3.0 Hz) mp:149(decomp.) 310 2 ESI+: 367 NMR: 0.43-0.47(2H, m), 1.03-1.07(2H, m),1.63-1.70(1H, m), 2.83-2.86(2H, m), 2.99- 3.05(4H, m), 3.18-3.22(4H, m),3.35-3.38(2H, m), 4.05-4.07(2H, m), 4.58(2H, t, J = 6.1 Hz), 6.42(2H,s), 6.52(1H, s), 7.14(1H, t, J = 4.8 Hz), 8.60(2H, d, J = 4.8 Hz) mp:188(decomp.) 311 2 ESI+: 386 NMR: 0.42-0.46(2H, m), 1.01(6H, d, J = 6.3Hz), 1.60-1.69(3H, m), 2.57-2.61(2H, m), 2.71-2.74(2H, m), 2.88-2.90(2H,m), 3.03-3.11(8H, m), 3.23-3.24(2H, m), 3.41-3.50(4H, m), 4.01-4.03(2H,m), 6.48(3H, s), 6.52(1H, s) mp: 129(decomp.) 312 2 ESI+: 371 NMR:0.49-0.60(2H, m), 0.85-1.00(2H, m), 1.61-1.74(1H, m), 2.78-3.07(8H, m),3.13- 3.27(2H, m), 3.87-4.00(2H, m), 4.17(2H, s), 6.38(1H, s), 6.55(1H,s), 7.25-7.51(3H, m) mp: 230(decomp.) 313 2 ESI+: 371 NMR: 0.49-0.60(2H,m), 0.85-0.95(2H, m), 1.62-1.72(1H, m), 2.81-3.06(8H, m), 3.17- 3.25(2H,m), 3.92-4.01(2H, m), 4.21(2H, s), 6.38(1H, s), 6.56(1H, s),7.09-7.22(3H, m) mp: 191-194 314 2 ESI+: 459 NMR: 0.43-0.47(2H, m),0.95-1.00(2H, m), 1.15(3H, t, J = 7.0 Hz), 1.53-1.60(1H, m), 2.85-2.87(2H, m), 3.00-3.05(4H, m), 3.17-3.22(4H, m), 3.31-3.34(2H, m),3.47(2H, q, J = 7.0 Hz), 4.05-4.07(2H, m), 4.38-4.40(4H, m), 6.42(2H,s), 6.53(1H, s), 7.06-7.12(2H, m) mp: 138-139 315 2 ESI+: 331 NMR:0.30-0.42(1H, m), 0.46-0.59(1H, m), 0.93-1.12(8H, m), 1.53-1.65(1H, m),2.79- 3.58(14H, m), 3.71-3.83(1H, m), 3.94-4.12(2H, m), 6.42(2H, s),6.50(1H, s) mp: 157-160 316 2 ESI+: 317 NMR: 0.14-0.27(1H, m),0.57-0.68(1H, m), 0.91(3H, d, J = 6.9 Hz), 0.96-1.09(2H, m), 1.55-1.68(1H, m), 2.76-3.19(9H, m), 3.25(3H, s), 3.28-3.48(2H, m), 3.61(2H,t, J = 6.1 Hz), 3.80-3.97(2H, m), 6.43(2H, s), 6.52(1H, s) mp:186(decomp)

TABLE 181 Ex Syn Dat 317 2 ESI+: 349 NMR: 0.32-0.43(1H, m),0.44-0.55(1H, m), 0.93-1.15(5H, m), 1.55- 1.67(1H, m), 2.82-2.92(2H, m),2.94-3.30(9H, m), 3.33-3.48(2H, m), 3.57- 3.67(1H, m), 3.79-3.94(1H, m),3.98-4.13(2H, m), 4.31- 4.60(2H, m), 6.43(2H, s), 6.52(1H, s) 318 2ESI+: 291 NMR: 0.91(3H, d, J = 6.8 Hz), 2.01-2.15(1H, m), 2.83-3.31(17H,m), 4.05- 4.14(2H, m), 6.51(1H, s), 6.52(1H, s), 9.24-9.50(2H, br) mp:129-132 319 2 ESI+: 277 NMR: 1.1(3H, t, J = 6.2 Hz), 2.85-2.93(2H, m),2.93-3.00(2H, m), 3.01- 3.12(4H, m), 3.12-3.46(7H, m), 3.53-3.64(1H, m),4.02- 4.13(2H, m), 6.52(1H, s), 6.54(1H, s), 9.32-9.48(2H, br)

TABLE 182

TABLE 183

TABLE 184

TABLE 185

TABLE 186

TABLE 187

TABLE 188

TABLE 189

TABLE 190

INDUSTRIAL APPLICABILITY

The compound of the formula (I) or a salt thereof, or the compound ofthe formula (II) or a salt thereof has a 5-HT_(2C) receptor agonistactivity and can be used as an agent for preventing or treating5-HT_(2C) receptor-related diseases.

Here, examples of the 5-HT_(2C) receptor-related diseases includeincontinence such as stress urinary incontinence, urge urinaryincontinence, mixed urinary incontinence, and the like, sexualdysfunction such as erectile dysfunction syndrome and the like, obesity,and the like.

The invention claimed is:
 1. A compound or a salt thereof, which is11-cyclopropyl-1-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline,4-(3-methoxypropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,5-cyclopropyl-4-[(2R)-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,5-cyclopropyl-4-[(2S)-3-fluoro-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,or5-cyclopropyl-4-(3-methylbenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,or a salt thereof.
 2. A pharmaceutical composition comprising a compoundor a salt thereof of claim 1 and a pharmaceutically acceptableexcipient.
 3. A method for treating stress urinary incontinence andmixed urinary incontinence, comprising administering to a subject aneffective amount of a compound or a salt thereof of claim
 1. 4. Acompound or a salt thereof of claim 1, which is11-cyclopropyl-1-(2-methoxyethyl)-2,3,4,6,7,8,9,10-octahydro-1H-azepino[4,5-g]quinoline,or a salt thereof.
 5. A compound or a salt thereof of claim 1, which is4-(3-methoxypropyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,or a salt thereof.
 6. A compound or a salt thereof of claim 1, which is5-cyclopropyl-4-[(2R)-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,or a salt thereof.
 7. A compound or a salt thereof of claim 1, which is5-cyclopropyl-4-[(2S)-3-fluoro-2-methoxypropyl]-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,or a salt thereof.
 8. A compound or a salt thereof of claim 1, which is5-cyclopropyl-4-(3-methylbenzyl)-2,3,4,6,7,8,9,10-octahydro[1,4]oxazino[2,3-h][3]benzazepine,or a salt thereof.